<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02211131</url>
  </required_header>
  <id_info>
    <org_study_id>20110266</org_study_id>
    <secondary_id>2014-001146-13</secondary_id>
    <nct_id>NCT02211131</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma</brief_title>
  <official_title>A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Amgen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of&#xD;
      talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery&#xD;
      alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of&#xD;
      talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery&#xD;
      alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.&#xD;
&#xD;
      Arm 1: Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor&#xD;
      lesion(s).&#xD;
&#xD;
      Arm 2: Immediate surgical resection of melanoma tumor lesion(s) Following surgery, adjuvant&#xD;
      systemic therapy and/or radiotherapy may be administered at the investigator's discretion and&#xD;
      per the institutional standard of care.&#xD;
&#xD;
      Subjects will be followed for safety approximately 30 (+15) days after surgery and for&#xD;
      disease recurrence, subsequent anticancer therapy, and survival every 3 months (±30 days) for&#xD;
      first 3 years after the end of the safety follow-up period and then every 6 months (±30 days)&#xD;
      until death, subject withdraws full consent, or up to 5 years after the last subject is&#xD;
      randomized.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 3, 2015</start_date>
  <completion_date type="Actual">April 28, 2022</completion_date>
  <primary_completion_date type="Actual">April 30, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recurrence-Free Survival (RFS)</measure>
    <time_frame>24 months after last participant was randomized (data cutoff date of 30 April 2019)</time_frame>
    <description>Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>RFS</measure>
    <time_frame>5 years after the last participant was randomized (last subject last visit occurred 28 April 2022)</time_frame>
    <description>Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year, 2 Years, 3 Years, and 5 Years</measure>
    <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
    <description>Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Histopathology Tumor-Free Margin (R0) Surgical Resection Rate</measure>
    <time_frame>18 weeks after last participant randomized (data cutoff date of 30 April 2019)</time_frame>
    <description>Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathological Complete Response (pCR) Rate</measure>
    <time_frame>18 weeks after last participant randomized (data cutoff date of 30 April 2019)</time_frame>
    <description>Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Local Recurrence-Free Survival (LRFS)</measure>
    <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
    <description>Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Regional Recurrence-Free Survival (RRFS)</measure>
    <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
    <description>Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distant Metastases-Free Survival (DMFS)</measure>
    <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
    <description>Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (Kaplan-Meier)</measure>
    <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
    <description>Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kaplan-Meier Estimate of OS at 1 Year, 2 Years, 3 Years, and 5 Years</measure>
    <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
    <description>Kaplan-Meier estimates of the percentage of participants alive at 1 year, 2 years, 3 years, and 5 years from randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best Overall Tumor Response Per Investigator Response Rate (Talimogene Laherparepvec Arm Only)</measure>
    <time_frame>18 months after last participant randomized (data cutoff date of 30 April 2019).</time_frame>
    <description>Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only)</measure>
    <time_frame>18 months after last participant randomized (data cutoff date of 30 April 2019).</time_frame>
    <description>The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only)</measure>
    <time_frame>18 months after last participant randomized (data cutoff date of 30 April 2019).</time_frame>
    <description>The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions</measure>
    <time_frame>Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks).</time_frame>
    <description>Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions</measure>
    <time_frame>Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</time_frame>
    <description>Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">150</enrollment>
  <condition>Completely Resectable Stage IIIB, IIIC, or IVM1a Melanoma</condition>
  <arm_group>
    <arm_group_label>Surgery</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Surgical resection of melanoma tumor lesion(s)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Talimogene Laherparepvec</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Talimogene Laherparepvec</intervention_name>
    <description>Talimogene laherparepvec will be administered by intralesional injection into the injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 10^6 plaque forming units (PFU)/mL at day 1 of week 1 followed by a dose of 10^8 PFU/mL at day 1 (±3 days) of week 4, 6, 8, 10 and 12 or until all injectable tumors have disappeared, or intolerance of study treatment or in the opinion of the investigator, immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first.</description>
    <arm_group_label>Talimogene Laherparepvec</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Immediate surgical resection of melanoma lesion(s)</intervention_name>
    <description>Surgical resection of melanoma tumor lesion(s) will be performed after randomization any time during weeks 1 to 6.</description>
    <arm_group_label>Surgery</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed diagnosis of stage IIIB, IIIC or IVM1a melanoma eligible for&#xD;
             complete surgical resection.&#xD;
&#xD;
          -  Prior systemic, regional and radiation anticancer therapies for melanoma must have&#xD;
             been completed at least 3 months prior to randomization.&#xD;
&#xD;
          -  Subject must have measurable disease and must be a candidate for intralesional therapy&#xD;
             with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10&#xD;
             mm in longest diameter) or with multiple injectable lesions that in aggregate have a&#xD;
             longest diameter of ≥ 10 mm.&#xD;
&#xD;
          -  Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0&#xD;
             or 1 and must have a serum lactate dehydrogenase (LDH) ≤ 1.0 X upper limit of normal&#xD;
             and adequate hematologic, hepatic, renal, and coagulation organ function- Other&#xD;
             criteria may apply&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject must not have primary ocular or mucosal melanoma, or history or evidence of&#xD;
             melanoma associated with immunodeficiency states (eg, hereditary immune deficiency,&#xD;
             organ transplant, or leukemia).&#xD;
&#xD;
          -  Subject must not have history or evidence of symptomatic autoimmune pneumonitis,&#xD;
             glomerulonephritis, vasculitis, or other symptomatic autoimmune disease.&#xD;
&#xD;
          -  Subject must not have evidence of clinically significant immunosuppression or active&#xD;
             herpetic skin lesions or prior complications of herpes simplex type 1 (HSV-1)&#xD;
             infection (eg, herpetic keratitis or encephalitis) and must not require intermittent&#xD;
             or chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than&#xD;
             intermittent topical use.&#xD;
&#xD;
          -  Subject known to have acute or chronic active hepatitis B, hepatitis C, or human&#xD;
             immunodeficiency virus infection will also be excluded.&#xD;
&#xD;
          -  Subject must not have been treated previously with talimogene laherparepvec or tumor&#xD;
             vaccine.&#xD;
&#xD;
        Other criteria may apply&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>MD</last_name>
    <role>Study Director</role>
    <affiliation>Amgen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35249</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <zip>90404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Daytona Beach</city>
        <state>Florida</state>
        <zip>32117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32610</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01655</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38163</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>North Sydney</city>
        <state>New South Wales</state>
        <zip>2060</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Woodville South</city>
        <state>South Australia</state>
        <zip>5011</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Florianopolis</city>
        <state>Santa Catarina</state>
        <zip>88034-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Barretos</city>
        <state>São Paulo</state>
        <zip>14784-400</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Rio de Janeiro</city>
        <zip>20220-410</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Dijon</city>
        <zip>21034</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Marseille cedex 05</city>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Pierre Benite Cedex</city>
        <zip>69495</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Toulouse cedex 9</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Athens</city>
        <zip>11527</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Heraklion - Crete</city>
        <zip>71110</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Poznan</city>
        <zip>60-856</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Warszawa</city>
        <zip>02-781</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Wroclaw</city>
        <zip>50-368</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Moscow</city>
        <zip>115478</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint-Petersburg</city>
        <zip>197022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint-Petersburg</city>
        <zip>197758</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Malaga</city>
        <state>Andalucía</state>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Pamplona</city>
        <state>Navarra</state>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madrid</city>
        <zip>28009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chur</city>
        <zip>7000</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Zürich</city>
        <zip>8091</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Brazil</country>
    <country>France</country>
    <country>Greece</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.amgentrials.com</url>
    <description>AmgenTrials clinical trials website</description>
  </link>
  <reference>
    <citation>Dummer R, Gyorki DE, Hyngstrom J, Berger AC, Conry R, Demidov L, Sharma A, Treichel SA, Radcliffe H, Gorski KS, Anderson A, Chan E, Faries M, Ross MI. Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial. Nat Med. 2021 Oct;27(10):1789-1796. doi: 10.1038/s41591-021-01510-7. Epub 2021 Oct 4.</citation>
    <PMID>34608333</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>August 5, 2014</study_first_submitted>
  <study_first_submitted_qc>August 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 7, 2014</study_first_posted>
  <results_first_submitted>April 21, 2020</results_first_submitted>
  <results_first_submitted_qc>May 20, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">May 28, 2020</results_first_posted>
  <disposition_first_submitted>April 9, 2020</disposition_first_submitted>
  <disposition_first_submitted_qc>April 9, 2020</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">April 14, 2020</disposition_first_posted>
  <last_update_submitted>May 9, 2023</last_update_submitted>
  <last_update_submitted_qc>May 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Talimogene laherparepvec</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.</ipd_time_frame>
    <ipd_access_criteria>Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.</ipd_access_criteria>
    <ipd_url>https://www.amgen.com/datasharing</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 23, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT02211131/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 14, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT02211131/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study was conducted at 35 centers in Australia, Brazil, Europe, Russia, and the United States. Participants were enrolled between 03 February 2015 and 28 April 2022.</recruitment_details>
      <pre_assignment_details>Participants were randomized 1:1 to receive either talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesions or immediate surgical resection of melanoma tumor lesion(s). Randomization was stratified by disease stage and planned adjuvant therapy.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Surgery</title>
          <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
        </group>
        <group group_id="P2">
          <title>Talimogene Laherparepvec Plus Surgery</title>
          <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="74"/>
                <participants group_id="P2" count="76"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="48"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="28"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Decision by Sponsor</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
      <group_list>
        <group group_id="B1">
          <title>Surgery</title>
          <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
        </group>
        <group group_id="B2">
          <title>Talimogene Laherparepvec Plus Surgery</title>
          <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="74"/>
            <count group_id="B2" value="76"/>
            <count group_id="B3" value="150"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.1" spread="16.1"/>
                    <measurement group_id="B2" value="62.6" spread="12.6"/>
                    <measurement group_id="B3" value="60.9" spread="14.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="54"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="49"/>
                    <measurement group_id="B3" value="96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="69"/>
                    <measurement group_id="B2" value="70"/>
                    <measurement group_id="B3" value="139"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="73"/>
                    <measurement group_id="B2" value="73"/>
                    <measurement group_id="B3" value="146"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Stratification Factor: Disease Stage</title>
          <description>The clinical participants were staged according to the American Joint Committee of Cancer (AJCC) 7th edition Melanoma Staging System, which combines tumor staging, nodal staging and metastasis to derive an overall stage. The order of prognostication is as follows: stage IIIB (better prognosis) &gt; stage IIIC &gt; stage IV M1a (worse prognosis).&#xD;
Randomization was stratified by disease stage and planned adjuvant therapy (adjuvant systemic therapy with or without radiotherapy vs radiotherapy without adjuvant systemic therapy vs none).</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Stage IIIB Nodal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stage IIIB In-Transit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stage IIIC Nodal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stage IIIC In-Transit With Nodal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stage IV M1a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Stratification Factor: Planned Adjuvant Therapy</title>
          <description>Randomization was stratified by disease stage (IIIB nodal vs IIIB in-transit vs IIIC nodal vs IIIC in-transit with nodal vs IVM1a) and planned adjuvant therapy (adjuvant systemic therapy with (W/) or without (W/O) radiotherapy vs radiotherapy without (W/O) adjuvant systemic therapy vs none).</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Adjuvant Systemic Therapy W/ or W/O Radiotherapy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Radiotherapy W/O Adjuvant Systemic Therapy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>None</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62"/>
                    <measurement group_id="B2" value="64"/>
                    <measurement group_id="B3" value="126"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Recurrence-Free Survival (RFS)</title>
        <description>Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.</description>
        <time_frame>24 months after last participant was randomized (data cutoff date of 30 April 2019)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Recurrence-Free Survival (RFS)</title>
          <description>Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="NA" upper_limit="NA">NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals (CIs) are not estimable.</measurement>
                    <measurement group_id="O2" value="0.0" lower_limit="0.0" upper_limit="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.070</p_value>
            <p_value_desc>Unstratified log-rank test</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.75</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.58</ci_lower_limit>
            <ci_upper_limit>0.96</ci_upper_limit>
            <estimate_desc>Unstratified Hazard Ratio (T-VEC + Surgery / Surgery)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>RFS</title>
        <description>Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.</description>
        <time_frame>5 years after the last participant was randomized (last subject last visit occurred 28 April 2022)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>RFS</title>
          <description>Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.03" lower_limit="NA" upper_limit="NA">NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals (CIs) are not estimable.</measurement>
                    <measurement group_id="O2" value="0.03" lower_limit="0.03" upper_limit="6.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.092</p_value>
            <p_value_desc>Unstratified log-rank test</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.76</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.60</ci_lower_limit>
            <ci_upper_limit>0.97</ci_upper_limit>
            <estimate_desc>Unstratified Hazard Ratio (T-VEC + Surgery / Surgery)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year, 2 Years, 3 Years, and 5 Years</title>
        <description>Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.</description>
        <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year, 2 Years, 3 Years, and 5 Years</title>
          <description>Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>RFS at 1 Year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.95" lower_limit="15.88" upper_limit="28.65"/>
                    <measurement group_id="O2" value="33.73" lower_limit="26.82" upper_limit="40.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RFS at 2 Years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.88" lower_limit="11.44" upper_limit="23.23"/>
                    <measurement group_id="O2" value="29.51" lower_limit="22.91" upper_limit="36.40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RFS at 3 Years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.88" lower_limit="11.44" upper_limit="23.23"/>
                    <measurement group_id="O2" value="28.11" lower_limit="21.62" upper_limit="36.94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RFS at 5 Years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.19" lower_limit="10.01" upper_limit="21.38"/>
                    <measurement group_id="O2" value="22.32" lower_limit="16.39" upper_limit="28.84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Histopathology Tumor-Free Margin (R0) Surgical Resection Rate</title>
        <description>Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.</description>
        <time_frame>18 weeks after last participant randomized (data cutoff date of 30 April 2019)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Histopathology Tumor-Free Margin (R0) Surgical Resection Rate</title>
          <description>Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.8" lower_limit="30.3" upper_limit="45.9"/>
                    <measurement group_id="O2" value="42.1" lower_limit="34.4" upper_limit="50.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.594</p_value>
            <p_value_desc>The two-sided p-value is based on the Pearson's Chi-square test.</p_value_desc>
            <method>Chi-squared</method>
            <param_type>Treatment Difference</param_type>
            <param_value>4.3</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-6.9</ci_lower_limit>
            <ci_upper_limit>15.3</ci_upper_limit>
            <estimate_desc>An 80% approximate exact CI for between-arm differences in binary rate is calculated using Wilson's score method with continuity correction.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pathological Complete Response (pCR) Rate</title>
        <description>Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.</description>
        <time_frame>18 weeks after last participant randomized (data cutoff date of 30 April 2019)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Pathological Complete Response (pCR) Rate</title>
          <description>Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.7" lower_limit="0.7" upper_limit="7.0"/>
                    <measurement group_id="O2" value="17.1" lower_limit="11.6" upper_limit="24.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.003</p_value>
            <p_value_desc>The two-sided p-value is based on the Pearson's Chi-square test.</p_value_desc>
            <method>Chi-squared</method>
            <param_type>Treatment Difference</param_type>
            <param_value>14.4</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>7.4</ci_lower_limit>
            <ci_upper_limit>21.6</ci_upper_limit>
            <estimate_desc>80% exact CI for binary rate of each arm is calculated using the Clopper Pearson method.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Local Recurrence-Free Survival (LRFS)</title>
        <description>Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.</description>
        <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Local Recurrence-Free Survival (LRFS)</title>
          <description>Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="NA" upper_limit="NA">NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals are not estimable.</measurement>
                    <measurement group_id="O2" value="0.0" lower_limit="0.0" upper_limit="7.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Regional Recurrence-Free Survival (RRFS)</title>
        <description>Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.</description>
        <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Regional Recurrence-Free Survival (RRFS)</title>
          <description>Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="NA" upper_limit="NA">NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals are not estimable.</measurement>
                    <measurement group_id="O2" value="0.0" lower_limit="0.0" upper_limit="12.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Distant Metastases-Free Survival (DMFS)</title>
        <description>Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.</description>
        <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Distant Metastases-Free Survival (DMFS)</title>
          <description>Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="NA" upper_limit="NA">NA = not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals are not estimable.</measurement>
                    <measurement group_id="O2" value="0.0" lower_limit="0.0" upper_limit="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (Kaplan-Meier)</title>
        <description>Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause.</description>
        <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (Kaplan-Meier)</title>
          <description>Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">NA=not estimable. Not enough events occurred to estimate the median and the confidence intervals.</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence interval is not estimable.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Kaplan-Meier Estimate of OS at 1 Year, 2 Years, 3 Years, and 5 Years</title>
        <description>Kaplan-Meier estimates of the percentage of participants alive at 1 year, 2 years, 3 years, and 5 years from randomization.</description>
        <time_frame>5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Kaplan-Meier Estimate of OS at 1 Year, 2 Years, 3 Years, and 5 Years</title>
          <description>Kaplan-Meier estimates of the percentage of participants alive at 1 year, 2 years, 3 years, and 5 years from randomization.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Year 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.92" lower_limit="79.63" upper_limit="90.38"/>
                    <measurement group_id="O2" value="95.89" lower_limit="91.58" upper_limit="98.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Year 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.44" lower_limit="70.29" upper_limit="83.08"/>
                    <measurement group_id="O2" value="88.94" lower_limit="83.16" upper_limit="92.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Year 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="71.59" lower_limit="64.03" upper_limit="77.84"/>
                    <measurement group_id="O2" value="83.27" lower_limit="76.70" upper_limit="88.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Year 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="62.29" lower_limit="54.75" upper_limit="69.62"/>
                    <measurement group_id="O2" value="77.32" lower_limit="70.12" upper_limit="83.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.050</p_value>
            <p_value_desc>Unstratified log-rank test</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.54</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.36</ci_lower_limit>
            <ci_upper_limit>0.81</ci_upper_limit>
            <estimate_desc>Unstratified Hazard Ratio (T-VEC + Surgery / Surgery)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Best Overall Tumor Response Per Investigator Response Rate (Talimogene Laherparepvec Arm Only)</title>
        <description>Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.</description>
        <time_frame>18 months after last participant randomized (data cutoff date of 30 April 2019).</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Best Overall Tumor Response Per Investigator Response Rate (Talimogene Laherparepvec Arm Only)</title>
          <description>Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.2" lower_limit="8.3" upper_limit="19.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only)</title>
        <description>The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.</description>
        <time_frame>18 months after last participant randomized (data cutoff date of 30 April 2019).</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only)</title>
          <description>The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>percentage of lesions</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.3" lower_limit="19.7" upper_limit="33.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only)</title>
        <description>The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.</description>
        <time_frame>18 months after last participant randomized (data cutoff date of 30 April 2019).</time_frame>
        <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only)</title>
          <description>The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.</description>
          <population>Intent to Treat Analysis Set: all participants who were randomized to either treatment group.</population>
          <units>percentage of lesions</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.9" lower_limit="1.5" upper_limit="8.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions</title>
        <description>Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</description>
        <time_frame>Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks).</time_frame>
        <population>Safety Analysis Set: all participants who received talimogene laherparepvec (TL) or surgical resection of melanoma tumor lesion(s).</population>
        <group_list>
          <group group_id="O1">
            <title>Surgery</title>
            <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec: Pre-Surgery</title>
            <description>Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).&#xD;
Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.</description>
          </group>
          <group group_id="O3">
            <title>Talimogene Laherparepvec: Post-Surgery</title>
            <description>Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).&#xD;
Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.</description>
          </group>
          <group group_id="O4">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions</title>
          <description>Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</description>
          <population>Safety Analysis Set: all participants who received talimogene laherparepvec (TL) or surgical resection of melanoma tumor lesion(s).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="69"/>
                <count group_id="O2" value="57"/>
                <count group_id="O3" value="57"/>
                <count group_id="O4" value="73"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>All TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32"/>
                    <measurement group_id="O2" value="53"/>
                    <measurement group_id="O3" value="19"/>
                    <measurement group_id="O4" value="70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="20"/>
                    <measurement group_id="O3" value="12"/>
                    <measurement group_id="O4" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="7"/>
                    <measurement group_id="O4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="8"/>
                    <measurement group_id="O4" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to DC of TL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">no TL administered</measurement>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to Interruption of TL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">no TL administered</measurement>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to &lt;4 ml TL Administered</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">no TL administered</measurement>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to &lt;4 ml TL Administered: Serious</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">no TL administered</measurement>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to &lt;4 ml TL Administered: Nonserious</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">no TL administered</measurement>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fatal Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions</title>
        <description>Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</description>
        <time_frame>Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</time_frame>
        <population>Safety Analysis Set: all participants who received talimogene laherparepvec (TL).</population>
        <group_list>
          <group group_id="O1">
            <title>Talimogene Laherparepvec: Pre-Surgery</title>
            <description>Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).&#xD;
Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.</description>
          </group>
          <group group_id="O2">
            <title>Talimogene Laherparepvec: Post-Surgery</title>
            <description>Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).&#xD;
Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.</description>
          </group>
          <group group_id="O3">
            <title>Talimogene Laherparepvec Plus Surgery</title>
            <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions</title>
          <description>Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.</description>
          <population>Safety Analysis Set: all participants who received talimogene laherparepvec (TL).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="57"/>
                <count group_id="O2" value="57"/>
                <count group_id="O3" value="73"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>All TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to DC of TL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to Interruption of TL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to &lt;4 ml TL Administered</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to &lt;4 ml TL Administered: Serious</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to &lt;4 ml TL Administered: Nonserious</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fatal Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks). All-cause mortality was reported from enrollment through end of follow-up (up to 5 years after randomization).</time_frame>
      <desc>All-cause mortality is reported for all participants enrolled in the study. Serious adverse events and other adverse events are reported for all randomized subjects who received talimogene laherparepvec or surgical resection of melanoma tumor lesion(s).</desc>
      <group_list>
        <group group_id="E1">
          <title>Surgery</title>
          <description>Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.</description>
        </group>
        <group group_id="E2">
          <title>TALIMOGENE LAHERPAREPVEC PLUS SURGERY</title>
          <description>Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.&#xD;
Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 24.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="26" subjects_at_risk="74"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="76"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Small intestinal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Postoperative wound infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Wound abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Glioblastoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebral ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Pregnancy, puerperium and perinatal conditions</title>
            <event_list>
              <event>
                <sub_title>Anembryonic gestation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Product Issues</title>
            <event_list>
              <event>
                <sub_title>Device occlusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Neck dissection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral embolism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 24.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="62" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Injection site erythema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Injection site pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="24" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="73"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="73"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Amgen Inc.</organization>
      <phone>866-572-6436</phone>
      <email>medinfo@amgen.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02211131
org study id: 20110266
secondary id: 2014-001146-13
nct id: NCT02211131
lead sponsor: 
has dmc: No
This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of
      talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery
      alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.
This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of
      talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery
      alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.

      Arm 1: Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor
      lesion(s).

      Arm 2: Immediate surgical resection of melanoma tumor lesion(s) Following surgery, adjuvant
      systemic therapy and/or radiotherapy may be administered at the investigator's discretion and
      per the institutional standard of care.

      Subjects will be followed for safety approximately 30 (+15) days after surgery and for
      disease recurrence, subsequent anticancer therapy, and survival every 3 months (±30 days) for
      first 3 years after the end of the safety follow-up period and then every 6 months (±30 days)
      until death, subject withdraws full consent, or up to 5 years after the last subject is
      randomized.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recurrence-Free Survival (RFS)
time frame: 24 months after last participant was randomized (data cutoff date of 30 April 2019)
description: Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.
measure: RFS
time frame: 5 years after the last participant was randomized (last subject last visit occurred 28 April 2022)
description: Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.
measure: Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year, 2 Years, 3 Years, and 5 Years
time frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
description: Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.
measure: Histopathology Tumor-Free Margin (R0) Surgical Resection Rate
time frame: 18 weeks after last participant randomized (data cutoff date of 30 April 2019)
description: Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.
measure: Pathological Complete Response (pCR) Rate
time frame: 18 weeks after last participant randomized (data cutoff date of 30 April 2019)
description: Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.
measure: Local Recurrence-Free Survival (LRFS)
time frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
description: Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.
measure: Regional Recurrence-Free Survival (RRFS)
time frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
description: Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.
measure: Distant Metastases-Free Survival (DMFS)
time frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
description: Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.
measure: Overall Survival (Kaplan-Meier)
time frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
description: Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause.
measure: Kaplan-Meier Estimate of OS at 1 Year, 2 Years, 3 Years, and 5 Years
time frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
description: Kaplan-Meier estimates of the percentage of participants alive at 1 year, 2 years, 3 years, and 5 years from randomization.
measure: Best Overall Tumor Response Per Investigator Response Rate (Talimogene Laherparepvec Arm Only)
time frame: 18 months after last participant randomized (data cutoff date of 30 April 2019).
description: Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.
measure: Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only)
time frame: 18 months after last participant randomized (data cutoff date of 30 April 2019).
description: The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
measure: Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only)
time frame: 18 months after last participant randomized (data cutoff date of 30 April 2019).
description: The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions
time frame: Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks).
description: Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
measure: Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions
time frame: Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
description: Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
arm group label: Surgery
arm group type: Other
description: Surgical resection of melanoma tumor lesion(s)
arm group label: Talimogene Laherparepvec
arm group type: Experimental
description: Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).
intervention type: Drug
intervention name: Talimogene Laherparepvec
description: Talimogene laherparepvec will be administered by intralesional injection into the injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 10^6 plaque forming units (PFU)/mL at day 1 of week 1 followed by a dose of 10^8 PFU/mL at day 1 (±3 days) of week 4, 6, 8, 10 and 12 or until all injectable tumors have disappeared, or intolerance of study treatment or in the opinion of the investigator, immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first.
arm group label: Talimogene Laherparepvec
intervention type: Procedure
intervention name: Immediate surgical resection of melanoma lesion(s)
description: Surgical resection of melanoma tumor lesion(s) will be performed after randomization any time during weeks 1 to 6.
arm group label: Surgery
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: MD
role: Study Director
affiliation: Amgen
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country: Australia
country: Brazil
country: France
country: Greece
country: Poland
country: Russian Federation
country: Spain
country: Switzerland
country: United States
url: http://www.amgentrials.com
description: AmgenTrials clinical trials website
citation: Dummer R, Gyorki DE, Hyngstrom J, Berger AC, Conry R, Demidov L, Sharma A, Treichel SA, Radcliffe H, Gorski KS, Anderson A, Chan E, Faries M, Ross MI. Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial. Nat Med. 2021 Oct;27(10):1789-1796. doi: 10.1038/s41591-021-01510-7. Epub 2021 Oct 4.
PMID: 34608333
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Talimogene laherparepvec
sharing ipd: Yes
ipd description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
ipd access criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
ipd url: https://www.amgen.com/datasharing
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reported events: 
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