<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/NCT03278405</url>
  </required_header>
  <id_info>
    <org_study_id>415-2016</org_study_id>
    <nct_id>NCT03278405</nct_id>
  </id_info>
  <brief_title>Avelumab in G3 NEC</brief_title>
  <acronym>NET-001</acronym>
  <official_title>A Pilot Study of Avelumab in Unresectable/Metastatic, Progressive, Poorly Differentiated Grade 3 Neuroendocrine Carcinomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sunnybrook Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck KGaA, Darmstadt, Germany</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sunnybrook Health Sciences Centre</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single-center, single-arm, open-label, pilot trial to evaluate the efficacy and&#xD;
      safety of avelumab in subjects with unresectable or metastatic, Grade 3,&#xD;
      poorly-differentiated neuroendocrine.carcinoma.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 15, 2017</start_date>
  <completion_date type="Actual">March 12, 2020</completion_date>
  <primary_completion_date type="Actual">August 9, 2019</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Overall response rate (ORR)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The overall response rate will be defined as the number of participants with confirmed complete response or partial response (CR or PR) recorded as the best response over the study period, divided by the number of participants evaluable for response as defined by RECIST version 1.1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Disease control rate (DCR)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The DCR will be defined as the number of patients with confirmed CR, PR or stable disease (SD) recorded as the best response over the study period, divided by the number of participants evaluable for response as defined by RECIST version 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Time from documentation of tumour response to disease progression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>PFS is defined as the time from first administration of study drug to the date of documented confirmed progression or death, whichever comes first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>OS is defined as the time from first administration of drug to date of death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rates of treatment-emergent adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03</measure>
    <time_frame>Up to 90 days after the last dose is administered</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ORR by irRECIST version 1.1</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DCR by irRECIST version 1.1</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response by irRECIST version 1.1</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS by irRECIST version 1.1</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS at 1 year</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS at 2 years</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS at 1 year</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS at 2 years</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation of PD-L1 status with response to avelumab</measure>
    <time_frame>Up to 2 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of mutational load and T-cell repertoire analysis with response to avelumab</measure>
    <time_frame>Up to 2 years</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Neuroendocrine Carcinoma</condition>
  <arm_group>
    <arm_group_label>Intervention Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment with avelumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>Avelumab will be administered intravenously as an infusion, at a dose of 10 milligram per kilogram once every 2 weeks, until occurence of progressive disease, unacceptable toxicity, or any of the other criteria for withdrawal listed in the protocol .</description>
    <arm_group_label>Intervention Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults (males or females), aged 18 years or older with pathologically confirmed,&#xD;
             advanced (unresectable or metastatic) neuroendocrine tumour from a&#xD;
             gastroenteropancreatic or lung source. Both participants with functional NETs and&#xD;
             those with nonfunctional NETs shall be eligible for this study.&#xD;
&#xD;
          -  Histologically confirmed, WHO Grade 3, poorly-differentiated NEC.&#xD;
&#xD;
          -  Has received 0,1 or 2 prior lines of systemic therapy (chemotherapy, PRRT, targeted&#xD;
             therapies such as everolimus or sunitinib). Somatostatin analogues are not considered&#xD;
             a line of therapy for the purposes of this criterion.&#xD;
&#xD;
          -  Radiological documentation of disease progression within 24 weeks of study enrolment.&#xD;
             Disease progression must be demonstrated on two scans less than one year apart.&#xD;
&#xD;
               -  Participants previously treated with any systemic therapies are eligible to&#xD;
                  enroll if disease progression is documented during or after their last treatment.&#xD;
&#xD;
          -  Measurable disease as assessed by CT scan of the chest, abdomen and pelvis which is&#xD;
             suitable for accurate repeated measurements (according to RECIST v1.1).&#xD;
&#xD;
          -  ECOG performance status 0-2.&#xD;
&#xD;
          -  Adequate bone marrow function (ANC &gt; 1.5 x 109/L; Platelets &gt;100 x109/L; haemoglobin &gt;&#xD;
             90 g /L).&#xD;
&#xD;
          -  Adequate liver function defined by a total bilirubin level ≤1.5xULN and AST and ALT&#xD;
             levels ≤2.5xULN for participants (or AST and ALT levels ≤ 5xULN for participants with&#xD;
             documented metastatic disease to the liver).&#xD;
&#xD;
          -  Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min&#xD;
             according to the Cockcroft-Gault formula (or local institutional standard method).&#xD;
&#xD;
          -  Willing and able to comply with all study requirements, including timing and/or nature&#xD;
             of treatment and required assessments.&#xD;
&#xD;
          -  Signed, written informed consent.&#xD;
&#xD;
          -  Evidence of post-menopausal status, or negative urine or serum pregnancy test for&#xD;
             female pre-menopausal participants (within approximately 14 days prior to enrolment).&#xD;
             Women will be considered post-menopausal if they have been amenorrhoeic for 12 months&#xD;
             without an alternative medical explanation.&#xD;
&#xD;
          -  Highly effective contraception for both male and female participants if the risk of&#xD;
             conception exists (note: The effects of the IP on the developing human fetus are&#xD;
             unknown; thus, women of childbearing potential and men able to father a child must&#xD;
             agree to use 2 highly effective contraceptions, defined as methods with a failure rate&#xD;
             of less than 1% per year. Highly effective contraception is required at least 28 days&#xD;
             prior, throughout and for at least 60 days after avelumab treatment.)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Grade 1-2 NET, or Grade 3 well-differentiated neuroendocrine tumour, or mixed&#xD;
             adenoneuroendocrine carcinomas (MANEC)&#xD;
&#xD;
          -  NETs confirmed to be from a primary other than the gastrointestinal tract, pancreas or&#xD;
             lung.&#xD;
&#xD;
          -  Prior use of PD-1, PD-L1 or CTLA-4 inhibitors&#xD;
&#xD;
          -  Life expectancy of ≤3 months&#xD;
&#xD;
          -  Concurrent treatment with other anticancer therapy (except somatostatin analogues for&#xD;
             the purposes of functional control). Participants on somatostatin analogues for&#xD;
             anti-proliferative therapy should have this therapy ceased, and would be eligible for&#xD;
             enrolment if they have not received somatostatin analogues in the past 14 days.&#xD;
&#xD;
          -  Active autoimmune disease that might deteriorate when receiving an immunostimulatory&#xD;
             agent, with exception to:&#xD;
&#xD;
          -  Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not&#xD;
             requiring immunosuppressive treatment are eligible&#xD;
&#xD;
          -  Active infection requiring systemic therapy.&#xD;
&#xD;
          -  History of primary autoimmunodeficiency&#xD;
&#xD;
          -  Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,&#xD;
             inhaled, topical steroids, or local steroid injection (e.g., intra-articular&#xD;
             injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone&#xD;
             or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT&#xD;
             scan premedication)&#xD;
&#xD;
          -  Prior organ transplantation, including allogeneic stem cell transplantation&#xD;
&#xD;
          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular&#xD;
             accident/stroke (&lt; 6 months prior to enrollment), myocardial infarction (&lt; 6 months&#xD;
             prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart&#xD;
             Association Classification Class II), or serious cardiac arrhythmia requiring&#xD;
             medication.&#xD;
&#xD;
          -  Major surgery in the 2 weeks prior to randomization. Surgery with intent to debulk&#xD;
             metastatic disease is allowed, as long as there is sufficient residual disease for&#xD;
             RECIST measurements (see inclusion criteria 5).&#xD;
&#xD;
          -  Participants with prior or concurrent malignancy except for the following: adequately&#xD;
             treated basal cell or squamous cell skin cancer, or other adequately treated in situ&#xD;
             cancer, or any other cancer from which the patient has been disease free for three&#xD;
             years.&#xD;
&#xD;
          -  All participants with brain metastases and any of the following:&#xD;
&#xD;
               -  They have not received local treatment to known brain metastases&#xD;
&#xD;
               -  They have been clinically unstable in the 2 weeks prior to enrolment&#xD;
&#xD;
               -  Requirement for treatment with systemic steroids exceeding the equivalent of 10mg&#xD;
                  oral prednisone per day&#xD;
&#xD;
               -  Ongoing neurological symptoms related to brain metastases&#xD;
&#xD;
               -  Leptomeningeal metastases&#xD;
&#xD;
          -  Pregnancy, lactation, or inadequate contraception.&#xD;
&#xD;
          -  Significant acute or chronic infections including, among others:&#xD;
&#xD;
               -  Known history of positive test for human immunodeficiency virus (HIV) or known&#xD;
                  acquired immunodeficiency syndrome (AIDS)&#xD;
&#xD;
               -  Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV&#xD;
                  antibody tested positive)&#xD;
&#xD;
               -  Active tuberculosis&#xD;
&#xD;
               -  Testing for these diseases is not mandatory unless clinically indicated.&#xD;
&#xD;
          -  Known prior severe hypersensitivity to investigational product or any component in its&#xD;
             formulations, including known severe hypersensitivity reactions to monoclonal&#xD;
             antibodies (NCI CTCAE v4.03 Grade ≥ 3)&#xD;
&#xD;
          -  Persisting toxicity related to prior therapy of Grade &gt;1 NCI-CTCAE v 4.03; however,&#xD;
             alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety&#xD;
             risk based on investigator's judgment are acceptable.&#xD;
&#xD;
          -  Known alcohol or drug abuse&#xD;
&#xD;
          -  Other severe acute or chronic medical conditions including colitis, inflammatory bowel&#xD;
             disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent&#xD;
             (within the past year) or active suicidal ideation or behavior; or laboratory&#xD;
             abnormalities that may increase the risk associated with study participation or study&#xD;
             treatment administration or may interfere with the interpretation of study results&#xD;
             and, in the judgment of the investigator, would make the patient inappropriate for&#xD;
             entry into this study.&#xD;
&#xD;
          -  Any psychiatric condition that would prohibit the understanding or rendering of&#xD;
             informed consent&#xD;
&#xD;
          -  Vaccination within 4 weeks of the first dose of avelumab and while on trial, except&#xD;
             for administration of inactivated vaccines&#xD;
&#xD;
          -  Inability to obtain sufficient tumour tissue (whether archival or fresh) for PD-L1&#xD;
             testing. A core biopsy, endoscopic biopsy or surgical resection specimen shall be&#xD;
             considered adequate tissue; a fine needle aspirate/biopsy will be considered&#xD;
             insufficient tissue.&#xD;
&#xD;
          -  Prior treatment for study indication with:&#xD;
&#xD;
               -  Peptide Receptor Radiouclide Therapy (PRRT) administered within 3 months of&#xD;
                  enrolment&#xD;
&#xD;
               -  Hepatic intra-arterial embolization, radio-frequency ablation, or cryoablation&#xD;
                  within 4 weeks of enrolment&#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>Simron Singh</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sunnybrook Health Sciences Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 11, 2017</study_first_posted>
  <last_update_submitted>March 17, 2020</last_update_submitted>
  <last_update_submitted_qc>March 17, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 18, 2020</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>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Neuroendocrine</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Avelumab</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03278405
org study id: 415-2016
nct id: NCT03278405
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is a single-center, single-arm, open-label, pilot trial to evaluate the efficacy and
      safety of avelumab in subjects with unresectable or metastatic, Grade 3,
      poorly-differentiated neuroendocrine.carcinoma.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate (ORR)
time frame: Up to 2 years
description: The overall response rate will be defined as the number of participants with confirmed complete response or partial response (CR or PR) recorded as the best response over the study period, divided by the number of participants evaluable for response as defined by RECIST version 1.1.
measure: Disease control rate (DCR)
time frame: Up to 2 years
description: The DCR will be defined as the number of patients with confirmed CR, PR or stable disease (SD) recorded as the best response over the study period, divided by the number of participants evaluable for response as defined by RECIST version 1.1.
measure: Duration of response
time frame: Up to 2 years
description: Time from documentation of tumour response to disease progression
measure: Progression-free survival (PFS)
time frame: Up to 2 years
description: PFS is defined as the time from first administration of study drug to the date of documented confirmed progression or death, whichever comes first
measure: Overall survival (OS)
time frame: Up to 2 years
description: OS is defined as the time from first administration of drug to date of death.
measure: Rates of treatment-emergent adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03
time frame: Up to 90 days after the last dose is administered
measure: ORR by irRECIST version 1.1
time frame: Up to 2 years
measure: DCR by irRECIST version 1.1
time frame: Up to 2 years
measure: Duration of response by irRECIST version 1.1
time frame: Up to 2 years
measure: PFS by irRECIST version 1.1
time frame: Up to 2 years
measure: OS at 1 year
time frame: 1 year
measure: OS at 2 years
time frame: 2 years
measure: PFS at 1 year
time frame: 1 year
measure: PFS at 2 years
time frame: 2 years
measure: Correlation of PD-L1 status with response to avelumab
time frame: Up to 2 years
measure: Correlation of mutational load and T-cell repertoire analysis with response to avelumab
time frame: Up to 2 years
arm group label: Intervention Arm
arm group type: Experimental
description: Treatment with avelumab
intervention type: Drug
intervention name: Avelumab
description: Avelumab will be administered intravenously as an infusion, at a dose of 10 milligram per kilogram once every 2 weeks, until occurence of progressive disease, unacceptable toxicity, or any of the other criteria for withdrawal listed in the protocol .
arm group label: Intervention Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Simron Singh
role: Principal Investigator
affiliation: Sunnybrook Health Sciences Centre
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Neuroendocrine
mesh term: Avelumab