<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/NCT03300544</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2016-01844</org_study_id>
    <secondary_id>NCI-2016-01844</secondary_id>
    <secondary_id>NCI10058</secondary_id>
    <secondary_id>10058</secondary_id>
    <secondary_id>10058</secondary_id>
    <secondary_id>UM1CA186688</secondary_id>
    <nct_id>NCT03300544</nct_id>
  </id_info>
  <brief_title>Talimogene Laherparepvec, Chemotherapy, and Radiation Therapy Before Surgery in Treating Patients With Locally Advanced or Metastatic Rectal Cancer</brief_title>
  <official_title>A Phase I Study of Talimogene Laherparepvec (Talimogene Laherparepvec) With Neoadjuvant Chemotherapy and Radiation in Adenocarcinoma of the Rectum</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the best dose and side effects of talimogene laherparepvec in&#xD;
      combination with 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, and chemoradiation&#xD;
      before surgery in treating patients with rectal cancer that has spread from where it started&#xD;
      to nearby tissue and lymph nodes. Drugs used in immunotherapy, such as talimogene&#xD;
      laherparepvec, may stimulate the body's immune system to fight tumor cells. Drugs used in&#xD;
      chemotherapy, such as 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine work in&#xD;
      different ways to stop the growth of tumor cells, either by killing the cells, by stopping&#xD;
      them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy&#xD;
      x-rays to kill tumor cells and shrink tumors. Giving talimogene laherparepvec,&#xD;
      5-fluorouracil, leucovorin, oxaliplatin, and capecitabine and chemoradiation before surgery&#xD;
      may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of&#xD;
      talimogene laherparepvec in combination with chemotherapy and radiation in rectal cancer.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To establish safety and feasibility of the combination. II. To determine the neoadjuvant&#xD;
      rectal (NAR) score of talimogene laherparepvec with chemotherapy and radiation.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To correlate genomic information including RAS, RAF mutation status with response, disease&#xD;
      free survival (DFS) and/or overall survival (OS).&#xD;
&#xD;
      II. To determine immunomodulatory changes following talimogene laherparepvec, chemotherapy&#xD;
      and radiation treatment including proportions of immune cell infiltrates in serially&#xD;
      collected peripheral blood and/or frozen tumor samples (pre-, on treatment, and at post&#xD;
      progression).&#xD;
&#xD;
      III. To identify magnetic resonance imaging (MRI)-based features including MRI&#xD;
      circumferential margin (mrCRM) at baseline or post-therapy mrCRM, MRI tumor regression grade&#xD;
      (mrTRG) to define determinants of response, DFS and OS.&#xD;
&#xD;
      IV. To determine the disease free survival (DFS) and overall survival (OS) of talimogene&#xD;
      laherparepvec with chemotherapy and radiation in patients undergoing curative resection.&#xD;
&#xD;
      V. To determine the pathological complete response (pCR) rate of talimogene laherparepvec&#xD;
      with chemotherapy and radiation.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of talimogene laherparepvec.&#xD;
&#xD;
      Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and&#xD;
      8. Patients receive 5-fluorouracil intravenously (IV) by bolus and over 46 hours, leucovorin&#xD;
      IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive&#xD;
      capecitabine orally (PO) twice daily (BID) followed by radiation therapy for 28 fractions on&#xD;
      days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 30 days and up to 5 years&#xD;
      thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 20, 2017</start_date>
  <completion_date type="Anticipated">March 22, 2023</completion_date>
  <primary_completion_date type="Actual">March 22, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum tolerated dose of talimogene laherparepvec (TVEC) in combination with chemotherapy and radiation</measure>
    <time_frame>4 weeks after surgery</time_frame>
    <description>Assessed using the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of dose limiting toxicities of TVEC</measure>
    <time_frame>4 weeks after surgery</time_frame>
    <description>Defined as grade 3 or 4 toxicities assessed using the NCI CTCAE version 5.0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent of planned dose intensity</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Descriptive statistics will be used to report results.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathological complete response</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will be reported with proportions along with the appropriate confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease free survival</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will be reported using Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will be reported using Kaplan-Meier method.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Locally Advanced Rectal Adenocarcinoma</condition>
  <condition>Metastatic Rectal Adenocarcinoma</condition>
  <condition>Rectal Adenocarcinoma</condition>
  <condition>Stage III Rectal Cancer AJCC v7</condition>
  <condition>Stage IIIA Rectal Cancer AJCC v7</condition>
  <condition>Stage IIIB Rectal Cancer AJCC v7</condition>
  <condition>Stage IIIC Rectal Cancer AJCC v7</condition>
  <condition>Stage IV Rectal Cancer AJCC v7</condition>
  <condition>Stage IVA Rectal Cancer AJCC v7</condition>
  <condition>Stage IVB Rectal Cancer AJCC v7</condition>
  <arm_group>
    <arm_group_label>Treatment (T-VEC, capecitabine, chemoradiation)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and 8. Patients receive 5-fluorouracil IV by bolus and over 46 hours, leucovorin IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive capecitabine orally PO BID followed by radiation therapy for 28 fractions on days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (T-VEC, capecitabine, chemoradiation)</arm_group_label>
    <other_name>Ro 09-1978/000</other_name>
    <other_name>Xeloda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fluorouracil</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (T-VEC, capecitabine, chemoradiation)</arm_group_label>
    <other_name>5 Fluorouracil</other_name>
    <other_name>5 Fluorouracilum</other_name>
    <other_name>5 FU</other_name>
    <other_name>5-Fluoro-2,4(1H, 3H)-pyrimidinedione</other_name>
    <other_name>5-Fluorouracil</other_name>
    <other_name>5-Fluracil</other_name>
    <other_name>5-Fu</other_name>
    <other_name>5FU</other_name>
    <other_name>AccuSite</other_name>
    <other_name>Carac</other_name>
    <other_name>Fluoro Uracil</other_name>
    <other_name>Fluouracil</other_name>
    <other_name>Flurablastin</other_name>
    <other_name>Fluracedyl</other_name>
    <other_name>Fluracil</other_name>
    <other_name>Fluril</other_name>
    <other_name>Fluroblastin</other_name>
    <other_name>Ribofluor</other_name>
    <other_name>Ro 2-9757</other_name>
    <other_name>Ro-2-9757</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (T-VEC, capecitabine, chemoradiation)</arm_group_label>
    <other_name>Folinic acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (T-VEC, capecitabine, chemoradiation)</arm_group_label>
    <other_name>1-OHP</other_name>
    <other_name>Ai Heng</other_name>
    <other_name>Aiheng</other_name>
    <other_name>Dacotin</other_name>
    <other_name>Dacplat</other_name>
    <other_name>Diaminocyclohexane Oxalatoplatinum</other_name>
    <other_name>Eloxatin</other_name>
    <other_name>Eloxatine</other_name>
    <other_name>JM-83</other_name>
    <other_name>Oxalatoplatin</other_name>
    <other_name>Oxalatoplatinum</other_name>
    <other_name>RP 54780</other_name>
    <other_name>RP-54780</other_name>
    <other_name>SR-96669</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiation Therapy</intervention_name>
    <description>Undergo chemoradiation</description>
    <arm_group_label>Treatment (T-VEC, capecitabine, chemoradiation)</arm_group_label>
    <other_name>Cancer Radiotherapy</other_name>
    <other_name>ENERGY_TYPE</other_name>
    <other_name>Irradiate</other_name>
    <other_name>Irradiated</other_name>
    <other_name>Irradiation</other_name>
    <other_name>Radiation</other_name>
    <other_name>Radiation Therapy, NOS</other_name>
    <other_name>Radiotherapeutics</other_name>
    <other_name>Radiotherapy</other_name>
    <other_name>RT</other_name>
    <other_name>Therapy, Radiation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Talimogene Laherparepvec</intervention_name>
    <description>Given intralesionally</description>
    <arm_group_label>Treatment (T-VEC, capecitabine, chemoradiation)</arm_group_label>
    <other_name>ICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene</other_name>
    <other_name>Imlygic</other_name>
    <other_name>JS1 34.5-hGMCSF 47- pA-</other_name>
    <other_name>T-VEC</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  For dose escalation: Patients must have A) histologically or cytologically confirmed&#xD;
             low lying (up to 6 cm of anal verge) rectal adenocarcinoma eligible for radiation&#xD;
             therapy to rectal tumor, B) if the treatment is palliative in the metastatic setting,&#xD;
             no additional requirements for tumor size or nodal involvement is needed; C) if the&#xD;
             treatment is in the neoadjuvant setting, the tumor must ALSO be high-risk locally&#xD;
             advanced rectal cancer defined as T3-4, N+, and/or at risk for a positive radial&#xD;
             margin (as determined by the surgeon)&#xD;
&#xD;
          -  For dose expansion: Patients must have A) histologically or cytologically confirmed&#xD;
             rectal adenocarcinoma eligible for radiation therapy to rectal tumor irrespective of&#xD;
             location from anal verge, B) if the treatment is palliative in the metastatic setting,&#xD;
             no additional requirements for tumor size or nodal involvement is needed; C) if the&#xD;
             treatment is in the neoadjuvant setting, the tumor must ALSO be high-risk locally&#xD;
             advanced rectal cancer defined as T3-4, N+, and/or at risk for a positive radial&#xD;
             margin (as determined by the surgeon)&#xD;
&#xD;
          -  Age &gt;= 18 years. Because no dosing or adverse event data are currently available on&#xD;
             the use of talimogene laherparepvec in combination with chemotherapy in patients &lt; 18&#xD;
             years of age&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1.5 x 10^9 /L&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
          -  Platelets &gt;= 100,000 x 10^9 /L&#xD;
&#xD;
          -  Serum bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN) (except patients&#xD;
             with Gilbert's syndrome, who can have total bilirubin &lt; 3 mg/DL)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =&lt; 2.5 x&#xD;
             institutional ULN&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault&#xD;
             formula) &gt;= 50 mL/min OR 24-hour urine creatinine clearance &gt;= 50 mL/min&#xD;
&#xD;
          -  Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin&#xD;
             time (PTT) =&lt; 1.5 x institutional unless the subject is on anticoagulant therapy (if&#xD;
             the subject is receiving anticoagulant therapy, PT, and activated partial&#xD;
             thromboplastin time [aPTT] must be within therapeutic range of intended use of&#xD;
             anticoagulants)&#xD;
&#xD;
          -  Patients must have signed informed consent indicating that they are aware of the&#xD;
             investigational nature of the study, and are aware that participation is voluntary;&#xD;
             patients must be made aware of their other treatment options&#xD;
&#xD;
          -  Talimogene laherparepvec, as well as other therapeutic agents used in this trial&#xD;
             including radiation and capecitabine, may cause fetal harm when administered to a&#xD;
             pregnant woman; women of childbearing potential (WOCBP) is defined as any female who&#xD;
             has experienced menarche and who has not undergone surgical sterilization&#xD;
             (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is&#xD;
             defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of&#xD;
             other biological or physiological causes; WOCBP and men must agree to use adequate&#xD;
             contraception (hormonal or barrier method of birth control; abstinence) prior to study&#xD;
             entry, during the study participation, and for four months after the last dose of the&#xD;
             drug; WOCBP must have a negative serum pregnancy test within 72 hours prior to&#xD;
             enrollment and agree to use effective contraception throughout the treatment period&#xD;
             and for 4 months after the last dose of study treatment; should a woman become&#xD;
             pregnant or suspect she is pregnant while she or her partner is participating in this&#xD;
             study, she should inform her treating physician immediately&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have had radiotherapy within &lt; 4 weeks are ineligible&#xD;
&#xD;
          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy&#xD;
             (i.e., have residual toxicities &gt; grade 1) except alopecia are ineligible&#xD;
&#xD;
          -  Use of other investigational, chemotherapeutic or targeted drugs within 28 days (or&#xD;
             five half-lives, whichever is shorter; with a minimum of 14 days from the last dose)&#xD;
             preceding the first dose of talimogene laherparepvec and during the study are&#xD;
             ineligible&#xD;
&#xD;
          -  Patients who have previously been treated with talimogene laherparepvec, any other&#xD;
             oncolytic virus or pelvic radiation are ineligible&#xD;
&#xD;
          -  Patients with known active central nervous system (CNS) metastases are ineligible;&#xD;
             subjects with previously treated brain metastases may participate provided they are&#xD;
             stable (without evidence of progression by imaging for at least four weeks prior to&#xD;
             the first dose of trial treatment and any neurologic symptoms have returned to&#xD;
             baseline), have no evidence of new or enlarging brain metastases&#xD;
&#xD;
          -  Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy&#xD;
             to talimogene laherparepvec or any of its components, capecitabine, fluorouracil&#xD;
             (5-FU) and / or oxaliplatin are ineligible&#xD;
&#xD;
          -  Patients with a history or evidence of active autoimmune disease (e.g., pneumonitis,&#xD;
             glomerulonephritis, vasculitis, or other); or history of active autoimmune disease&#xD;
             that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive&#xD;
             drugs or biological agents used for treatment of autoimmune diseases) within 2 months&#xD;
             of enrollment are ineligible; (replacement therapy [e.g., thyroxine for&#xD;
             hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy&#xD;
             for adrenal or pituitary insufficiency] is not considered a form of systemic treatment&#xD;
             for autoimmune disease)&#xD;
&#xD;
          -  Patients with evidence of clinically significant immunosuppression such as the&#xD;
             following are ineligible:&#xD;
&#xD;
               -  Primary immunodeficiency state such as severe combined immunodeficiency disease&#xD;
&#xD;
               -  Concurrent opportunistic infection&#xD;
&#xD;
               -  Receiving systemic immunosuppressive therapy (&gt; 2 weeks) including oral steroid&#xD;
                  doses &gt; 10 mg/day of prednisone or equivalent within 2 months prior to enrollment&#xD;
&#xD;
          -  Patients with active herpetic skin lesions or prior complications of herpetic&#xD;
             infection (e.g., herpetic keratitis or encephalitis) are ineligible&#xD;
&#xD;
          -  Patients with viral infections requiring intermittent or chronic systemic (intravenous&#xD;
             or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than&#xD;
             intermittent topical use are ineligible&#xD;
&#xD;
          -  Patients with other viral infections are ineligible:&#xD;
&#xD;
               -  Known to have acute or chronic active hepatitis B or hepatitis C infection&#xD;
&#xD;
               -  Known to have human immunodeficiency virus (HIV) infection&#xD;
&#xD;
               -  Prior therapy with viral-based tumor vaccine&#xD;
&#xD;
               -  Received live vaccine within 28 days prior to enrollment&#xD;
&#xD;
          -  Subject who is unwilling to minimize exposure with his/her blood or other body fluids&#xD;
             to individuals who are at higher risks for herpes simplex virus (HSV)-1 induced&#xD;
             complications such as immunosuppressed individuals, individuals known to have HIV&#xD;
             infection, pregnant women, or children under the age of 1 year, during talimogene&#xD;
             laherparepvec treatment and through 30 days after the last dose of talimogene&#xD;
             laherparepvec are ineligible&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness including, but not limited to, active,&#xD;
             non-colorectal malignancies requiring systemic therapy, ongoing or active infection,&#xD;
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements are ineligible&#xD;
&#xD;
          -  Although no effects on embryo-fetal development have been observed in animal studies,&#xD;
             adequate and well-controlled studies with talimogene laherparepvec have not been&#xD;
             conducted in pregnant women; in addition, given the high risk of detrimental effects&#xD;
             of other study agents including capecitabine, 5-FU, oxaliplatin and radiation on&#xD;
             embryo-fetal development, the study treatment must be excluded in the following&#xD;
             patients:&#xD;
&#xD;
               -  Female subject is pregnant or breast-feeding, or planning to become pregnant&#xD;
                  during study treatment and through 4 months after the last dose of talimogene&#xD;
                  laherparepvec&#xD;
&#xD;
               -  Female subject of childbearing potential who is unwilling to use acceptable&#xD;
                  method(s) of effective contraception during study treatment and through 4 months&#xD;
                  after the last dose of talimogene laherparepvec&#xD;
&#xD;
               -  Sexually active subjects and their partners unwilling to use male or female latex&#xD;
                  condom to avoid potential viral transmission during sexual contact while on&#xD;
                  treatment and within 30 days after treatment with talimogene laherparepvec&#xD;
&#xD;
          -  Patients that are unable to swallow oral medications are ineligible&#xD;
&#xD;
          -  Patients with a major surgical procedure, open biopsy, or significant traumatic injury&#xD;
             within 28 days prior to initiation of therapy, or anticipation of need for major&#xD;
             surgical procedure during the course of the study other than that defined by protocol&#xD;
             are ineligible&#xD;
&#xD;
          -  If patients require anticoagulation while on protocol, they should be switched from&#xD;
             warfarin to another alternative anticoagulant such as low molecular weight heparin or&#xD;
             oral direct factor Xa inhibitors as deemed appropriate by the treating physician for&#xD;
             the duration they are on capecitabine (must be switched at least 1 week prior to&#xD;
             starting capecitabine) to avoid drug-drug interaction of warfarin with capecitabine&#xD;
&#xD;
          -  Patients with a known dihydropyrimidine dehydrogenase (DPD) deficiency are ineligible&#xD;
&#xD;
          -  Patients who are unable to get MRIs due to any reason including pacemakers or&#xD;
             automatic implantable cardioverter-defibrillator (AICD) are ineligible&#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>Nageshwara V Dasari</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas MD Anderson Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>October 2, 2017</study_first_submitted>
  <study_first_submitted_qc>October 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 3, 2017</study_first_posted>
  <last_update_submitted>October 18, 2022</last_update_submitted>
  <last_update_submitted_qc>October 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 19, 2022</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>Adenocarcinoma</mesh_term>
    <mesh_term>Rectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Talimogene laherparepvec</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>March 16, 2023</submitted>
    <returned>April 10, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03300544
org study id: NCI-2016-01844
secondary id: NCI-2016-01844
secondary id: NCI10058
secondary id: 10058
secondary id: 10058
secondary id: UM1CA186688
nct id: NCT03300544
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the best dose and side effects of talimogene laherparepvec in
      combination with 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, and chemoradiation
      before surgery in treating patients with rectal cancer that has spread from where it started
      to nearby tissue and lymph nodes. Drugs used in immunotherapy, such as talimogene
      laherparepvec, may stimulate the body's immune system to fight tumor cells. Drugs used in
      chemotherapy, such as 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine work in
      different ways to stop the growth of tumor cells, either by killing the cells, by stopping
      them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy
      x-rays to kill tumor cells and shrink tumors. Giving talimogene laherparepvec,
      5-fluorouracil, leucovorin, oxaliplatin, and capecitabine and chemoradiation before surgery
      may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
PRIMARY OBJECTIVE:

      I. To determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of
      talimogene laherparepvec in combination with chemotherapy and radiation in rectal cancer.

      SECONDARY OBJECTIVES:

      I. To establish safety and feasibility of the combination. II. To determine the neoadjuvant
      rectal (NAR) score of talimogene laherparepvec with chemotherapy and radiation.

      EXPLORATORY OBJECTIVES:

      I. To correlate genomic information including RAS, RAF mutation status with response, disease
      free survival (DFS) and/or overall survival (OS).

      II. To determine immunomodulatory changes following talimogene laherparepvec, chemotherapy
      and radiation treatment including proportions of immune cell infiltrates in serially
      collected peripheral blood and/or frozen tumor samples (pre-, on treatment, and at post
      progression).

      III. To identify magnetic resonance imaging (MRI)-based features including MRI
      circumferential margin (mrCRM) at baseline or post-therapy mrCRM, MRI tumor regression grade
      (mrTRG) to define determinants of response, DFS and OS.

      IV. To determine the disease free survival (DFS) and overall survival (OS) of talimogene
      laherparepvec with chemotherapy and radiation in patients undergoing curative resection.

      V. To determine the pathological complete response (pCR) rate of talimogene laherparepvec
      with chemotherapy and radiation.

      OUTLINE: This is a dose-escalation study of talimogene laherparepvec.

      Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and
      8. Patients receive 5-fluorouracil intravenously (IV) by bolus and over 46 hours, leucovorin
      IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive
      capecitabine orally (PO) twice daily (BID) followed by radiation therapy for 28 fractions on
      days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.

      After completion of study treatment, patients are followed up for 30 days and up to 5 years
      thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of talimogene laherparepvec (TVEC) in combination with chemotherapy and radiation
time frame: 4 weeks after surgery
description: Assessed using the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0.
measure: Incidence of dose limiting toxicities of TVEC
time frame: 4 weeks after surgery
description: Defined as grade 3 or 4 toxicities assessed using the NCI CTCAE version 5.0.
measure: Percent of planned dose intensity
time frame: Up to 5 years
description: Descriptive statistics will be used to report results.
measure: Pathological complete response
time frame: Up to 5 years
description: Will be reported with proportions along with the appropriate confidence intervals.
measure: Disease free survival
time frame: Up to 5 years
description: Will be reported using Kaplan-Meier method.
measure: Overall survival
time frame: Up to 5 years
description: Will be reported using Kaplan-Meier method.
arm group label: Treatment (T-VEC, capecitabine, chemoradiation)
arm group type: Experimental
description: Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and 8. Patients receive 5-fluorouracil IV by bolus and over 46 hours, leucovorin IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive capecitabine orally PO BID followed by radiation therapy for 28 fractions on days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.
intervention type: Drug
intervention name: Capecitabine
description: Given PO
arm group label: Treatment (T-VEC, capecitabine, chemoradiation)
other name: Ro 09-1978/000
other name: Xeloda
intervention type: Drug
intervention name: Fluorouracil
description: Given IV
arm group label: Treatment (T-VEC, capecitabine, chemoradiation)
other name: 5 Fluorouracil
other name: 5 Fluorouracilum
other name: 5 FU
other name: 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
other name: 5-Fluorouracil
other name: 5-Fluracil
other name: 5-Fu
other name: 5FU
other name: AccuSite
other name: Carac
other name: Fluoro Uracil
other name: Fluouracil
other name: Flurablastin
other name: Fluracedyl
other name: Fluracil
other name: Fluril
other name: Fluroblastin
other name: Ribofluor
other name: Ro 2-9757
other name: Ro-2-9757
intervention type: Drug
intervention name: Leucovorin
description: Given IV
arm group label: Treatment (T-VEC, capecitabine, chemoradiation)
other name: Folinic acid
intervention type: Drug
intervention name: Oxaliplatin
description: Given IV
arm group label: Treatment (T-VEC, capecitabine, chemoradiation)
other name: 1-OHP
other name: Ai Heng
other name: Aiheng
other name: Dacotin
other name: Dacplat
other name: Diaminocyclohexane Oxalatoplatinum
other name: Eloxatin
other name: Eloxatine
other name: JM-83
other name: Oxalatoplatin
other name: Oxalatoplatinum
other name: RP 54780
other name: RP-54780
other name: SR-96669
intervention type: Radiation
intervention name: Radiation Therapy
description: Undergo chemoradiation
arm group label: Treatment (T-VEC, capecitabine, chemoradiation)
other name: Cancer Radiotherapy
other name: ENERGY_TYPE
other name: Irradiate
other name: Irradiated
other name: Irradiation
other name: Radiation
other name: Radiation Therapy, NOS
other name: Radiotherapeutics
other name: Radiotherapy
other name: RT
other name: Therapy, Radiation
intervention type: Biological
intervention name: Talimogene Laherparepvec
description: Given intralesionally
arm group label: Treatment (T-VEC, capecitabine, chemoradiation)
other name: ICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene
other name: Imlygic
other name: JS1 34.5-hGMCSF 47- pA-
other name: T-VEC
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nageshwara V Dasari
role: Principal Investigator
affiliation: University of Texas MD Anderson Cancer Center LAO
facility: 
country: United States
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Rectal Neoplasms
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Capecitabine
mesh term: Oxaliplatin
mesh term: Talimogene laherparepvec
submitted: March 16, 2023
returned: April 10, 2023