<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/NCT02993991</url>
  </required_header>
  <id_info>
    <org_study_id>PRIMED-001</org_study_id>
    <nct_id>NCT02993991</nct_id>
  </id_info>
  <brief_title>Pre-operative Mocetinostat (MGCD0103) and Durvalumab (MEDI4736) (PRIMED) for Squamous Cell Carcinoma of the Oral Cavity</brief_title>
  <acronym>PRIMED-001</acronym>
  <official_title>Pre-operative Mocetinostat (MGCD0103) and Durvalumab (MEDI4736) (PRIMED) for Squamous Cell Carcinoma of the Oral Cavity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Mirati Therapeutics Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>No</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 Phase 1 Window of Opportunity study to evaluate the pharmacodynamic and immune&#xD;
      effects of pre-operative therapy with Mocetinostat and Durvalumab on patients with squamous&#xD;
      cell carcinoma of the oral cavity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single center, open-label, non-randomized, pre-operative window of opportunity&#xD;
      study for patients with resectable squamous cell carcinoma of the oral cavity who are&#xD;
      considered suitable for curative-intent surgical resection, with pre-operative Mocetinostat&#xD;
      and Durvalumab.&#xD;
&#xD;
      This study will involve treatment with Mocetinostat and Durvalumab, tests and procedures done&#xD;
      for safety and the collection of blood samples for biomarker research. Tissue samples (fresh&#xD;
      biopsy or archival tissue) will also be collected for biomarker research and evaluation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    The study has been terminated due to a change in internal prioritization and not due to any&#xD;
    safety concerns.&#xD;
  </why_stopped>
  <start_date type="Anticipated">October 10, 2017</start_date>
  <completion_date type="Actual">December 21, 2017</completion_date>
  <primary_completion_date type="Actual">December 21, 2017</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>Pharmacodynamic effects with biomarker analyses (Tumor PD-L1 by IHC; Density of peri-tumoral and intra-tumoral CD3, CD4 and CD8-positive lymphocytes; Serum pro-inflammatory cytokines and chemokines)</measure>
    <time_frame>3 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Immune effects with biomarker analyses (Tumor PD-L1 by IHC; Density of peri-tumoral and intra-tumoral CD3, CD4 and CD8-positive lymphocytes; Serum pro-inflammatory cytokines and chemokines)</measure>
    <time_frame>3 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Toxicities as per NCI CTCAE v4.1</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of completion of surgery within the initially planned window as per RECIST v1.1</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of disease progression as per RECIST v1.1 during the pre-operative treatment period</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of post-operative complications as per NCI CTCAE v4.1</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Optimal biologically active dose of mocetinostat (Correlation of tumor and serum-based assessments with mocetinostat dose levels)</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in serum mocetinostat concentrations prior to and following durvalumab therapy</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Dynamic changes in immune cell activation and/or suppression using flow cytometry and DNA/RNA sequencing (tumor and immune cell genome and trascriptome analysis)</measure>
    <time_frame>3 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Dynamic changes in intratumoral hypoxia with pre-operative mocetinostat and durvalumab therapy using 18FAZA PET</measure>
    <time_frame>3 years</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Squamous Cell Carcinoma, Head And Neck</condition>
  <condition>Squamous Cell Carcinoma Mouth</condition>
  <condition>Resectable Squamous Cell Carcinoma of Oral Cavity</condition>
  <arm_group>
    <arm_group_label>Mocetinostat and Durvalumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will start therapy with mocetinostat within 10 days of study enrollment. Mocetinostat will be given in 2 dose levels (n = 6 evaluable patients each) of 70mg three-times weekly and 90mg three-times weekly for 2 weeks.&#xD;
Durvalumab will be given as a single infusion at a dose of 1500mg, over a period of 1-hour, on day 8 of the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mocetinostat</intervention_name>
    <description>Mocetinostat (MGCD0103) is a potent small molecule HDAC inhibitor that targets human HDAC isoforms. It is an orally bioavailable, second generation benzamide inhibitor of HDAC 1, 2, 3 and 11 with broad spectrum antitumor activity in vitro and in vivo.</description>
    <arm_group_label>Mocetinostat and Durvalumab</arm_group_label>
    <other_name>MGCD0103</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against human PD-L1. It is selective for recombinant PD-L1 and blocks the binding of recombinant PD-L1 to the PD-1 and CD80 receptors.</description>
    <arm_group_label>Mocetinostat and Durvalumab</arm_group_label>
    <other_name>MEDI4736</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed written and voluntary informed consent.&#xD;
&#xD;
          2. Patient must be willing and able to comply with scheduled visits, treatment plan,&#xD;
             laboratory tests and other study procedures.&#xD;
&#xD;
          3. Age &gt; 18 years, male or female. Disease characteristics&#xD;
&#xD;
          4. Patient must be diagnosed with histologically confirmed squamous cell carcinoma of the&#xD;
             oral cavity (SCCOC) (floor of mouth, anterior 2/3 tongue, buccal mucosa, upper and&#xD;
             lower gingiva, and retromolar trigone) considered resectable by the head and neck&#xD;
             surgical rounds (T2-4a, N0-2, M0; without evidence of distant metastasis).&#xD;
&#xD;
          5. Patient must be willing and able to provide up to 2 fresh tumor biopsies for&#xD;
             histopathological and biomarker evaluation; first as pre-treatment baseline, and the&#xD;
             second after treatment with mocetinostat but prior to treatment with durvalumab.&#xD;
&#xD;
               -  Patients who decline an in-house fresh pre-treatment tumor biopsy must give&#xD;
                  consent to provide a tumor block from an existing diagnostic primary tumor biopsy&#xD;
                  completed within 90 days of enrollment, which is of acceptable quality and&#xD;
                  quantity for analysis, as assessed by the study site correlatives team.&#xD;
&#xD;
          6. No anti-neoplastic treatment is allowed between the time from obtaining baseline tumor&#xD;
             specimen and enrollment.&#xD;
&#xD;
             Patient characteristics&#xD;
&#xD;
          7. ECOG performance status 0-1.&#xD;
&#xD;
          8. Patient must have adequate organ function as determined by the following:&#xD;
&#xD;
             - Renal function: i. Serum creatinine &lt; 1.5 ULN (upper limit of normal range) or a&#xD;
             calculated creatinine clearance of &gt; 50mL/min using the following formula: Creatinine&#xD;
             clearance = [(140-age) x wt (kg) x Constant*] / creatinine (umol/L)&#xD;
&#xD;
             *Constant = 1.23 for men, and 1.04 for women&#xD;
&#xD;
             - Bone marrow function (without hematopoietic growth factors or transfusion): i.&#xD;
             Absolute neutrophil count (ANC) &gt; 1.5 x 109/L ii. Leukocytes &gt; 3.0 x 109/L iii.&#xD;
             Hemoglobin &gt; 90 g/L or &gt; 9g/dL iv. Platelets &gt; 100 x 109/L&#xD;
&#xD;
             - Liver function: i. Total bilirubin &lt; ULN ii. Aspartate aminotransferase (AST/SGOT)&#xD;
             and alanine aminotransferase (ALT/SGPT) &lt; 2.5 x ULN&#xD;
&#xD;
             - Cardiac function: i. A normal left ventricular ejection fraction (LVEF) of &gt; 50% and&#xD;
             the absence of any clinically significant pericardial effusion, as evidenced by an&#xD;
             echocardiogram performed within 4 weeks of the study commencement.&#xD;
&#xD;
          9. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for&#xD;
             female pre-menopausal patients. Women will be considered post-menopausal if they have&#xD;
             been amenorrheic for 12 months without an alternative medical cause. The following&#xD;
             age-specific requirements apply:&#xD;
&#xD;
               -  Women &lt;50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of exogenous hormonal&#xD;
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone&#xD;
                  levels in the post-menopausal range for the institution or underwent surgical&#xD;
                  sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).&#xD;
&#xD;
               -  Women ≥50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal&#xD;
                  treatments, had radiation-induced menopause with last menses &gt;1 year ago, had&#xD;
                  chemotherapy-induced menopause with last menses &gt;1 year ago, or underwent&#xD;
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or&#xD;
                  hysterectomy).&#xD;
&#xD;
         10. Subject is willing and able to comply with the protocol for the duration of the study&#xD;
             including undergoing treatment and scheduled visits and examinations including follow&#xD;
             up.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Primary site of head and neck carcinoma unknown, lip, hard palate, skin, or outside&#xD;
             the oral cavity.&#xD;
&#xD;
          2. Patients with tumors that invade major vessels, as shown unequivocally by imaging&#xD;
             studies.&#xD;
&#xD;
               -  For patients with tumors that do not invade major blood vessels but are within&#xD;
                  3mm of the carotid artery or branches thereof, any anticoagulant therapy&#xD;
                  (including aspirin, non-steroidal anti-inflammatories, antiplatelet agents or&#xD;
                  other anti-coagulants) must be discontinued.&#xD;
&#xD;
          3. Patients with any prior history of bleeding related to the current head and neck&#xD;
             cancer.&#xD;
&#xD;
          4. Patients with a history of gross hemoptysis (bright red blood of ½ teaspoon or more&#xD;
             per episode of coughing) &lt; 3 months prior to enrollment.&#xD;
&#xD;
          5. Prior or concurrent radiation therapy to tumor at site of planned resection.&#xD;
&#xD;
          6. Any concurrent chemotherapy, biologic, immunologic or hormonal therapy for cancer&#xD;
             treatment.&#xD;
&#xD;
               -  Concurrent use of hormones for non-cancer-related conditions (eg, insulin for&#xD;
                  diabetes and hormone replacement therapy) is acceptable.&#xD;
&#xD;
          7. Current or prior use of immunosuppressive medication within 14 days prior to starting&#xD;
             dosing. The following are exceptions to this criteria:&#xD;
&#xD;
               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg,&#xD;
                  intra-articular injection).&#xD;
&#xD;
               -  Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of&#xD;
                  prednisone or equivalent.&#xD;
&#xD;
               -  Steroids as premedication for hypersensitivity reactions (eg, computed tomography&#xD;
                  scan premedication).&#xD;
&#xD;
          8. Active or documented history of autoimmune disease within 2 years before screening,&#xD;
             including:&#xD;
&#xD;
               -  Active or prior documented inflammatory bowel disease (eg. Crohn's disease,&#xD;
                  ulcerative colitis).&#xD;
&#xD;
               -  Patients with vitiligo, resolved childhood asthma/atopy, type I diabetes&#xD;
                  mellitus, Grave's disease, Hashimoto's disease, or psoriasis not requiring&#xD;
                  systemic treatment within the past 2 years, are not excluded.&#xD;
&#xD;
          9. History of primary immune deficiency.&#xD;
&#xD;
         10. History of organ transplant that requires use of immunosuppressive medications.&#xD;
&#xD;
         11. Use of any live vaccines against infectious diseases within 4 weeks of study treatment&#xD;
             initiation.&#xD;
&#xD;
         12. Known allergy or reaction to any component of Mocetinostat and/or Durvalumab&#xD;
             formulation.&#xD;
&#xD;
         13. Known history of tuberculosis.&#xD;
&#xD;
         14. Subjects who are known to be human immunodeficiency (HIV) positive.&#xD;
&#xD;
         15. Subjects who are known to be hepatitis B or C positive.&#xD;
&#xD;
         16. Female patients who are pregnant or breast-feeding.&#xD;
&#xD;
         17. Male or female patients of reproductive potential who are not willing to use effective&#xD;
             birth control from screening to 180 days following the last dose of durvalumab.&#xD;
&#xD;
         18. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable&#xD;
             angina pectoris, unstable cardiac arrhythmia, active peptic ulcer disease or&#xD;
             gastritis, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirement, substantially increase risk of incurring adverse events from&#xD;
             Mocetinostat or Durvalumab, or compromise the ability of the subject to give written&#xD;
             informed consent.&#xD;
&#xD;
         19. Any condition that, in the opinion of the Investigator, would interfere with&#xD;
             evaluation of the study regimen or interpretation of patient safety or study results.&#xD;
&#xD;
         20. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.&#xD;
&#xD;
         21. History of another primary malignancy, except for:&#xD;
&#xD;
               -  Malignancy treated with curative intent and with no known active disease ≥5 years&#xD;
                  before the first dose of study drug and of low potential risk for recurrence,&#xD;
&#xD;
               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence&#xD;
                  of disease,&#xD;
&#xD;
               -  Adequately treated carcinoma in situ without evidence of disease.&#xD;
&#xD;
         22. Major surgical procedure (as defined by the Investigator) within 28 days prior to the&#xD;
             first dose of study medications.&#xD;
&#xD;
         23. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous&#xD;
             immunotherapy agent, or any unresolved irAE &gt;Grade 1.&#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>Lillian Siu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Staff Physician and Medical Oncologist</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Princess Margaret Cancer Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>December 2017</verification_date>
  <study_first_submitted>December 1, 2016</study_first_submitted>
  <study_first_submitted_qc>December 13, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 15, 2016</study_first_posted>
  <last_update_submitted>December 27, 2017</last_update_submitted>
  <last_update_submitted_qc>December 27, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">December 29, 2017</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, Squamous Cell</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Mocetinostat</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/NCT02993991
org study id: PRIMED-001
nct id: NCT02993991
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is a Phase 1 Window of Opportunity study to evaluate the pharmacodynamic and immune
      effects of pre-operative therapy with Mocetinostat and Durvalumab on patients with squamous
      cell carcinoma of the oral cavity.
This is a single center, open-label, non-randomized, pre-operative window of opportunity
      study for patients with resectable squamous cell carcinoma of the oral cavity who are
      considered suitable for curative-intent surgical resection, with pre-operative Mocetinostat
      and Durvalumab.

      This study will involve treatment with Mocetinostat and Durvalumab, tests and procedures done
      for safety and the collection of blood samples for biomarker research. Tissue samples (fresh
      biopsy or archival tissue) will also be collected for biomarker research and evaluation.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pharmacodynamic effects with biomarker analyses (Tumor PD-L1 by IHC; Density of peri-tumoral and intra-tumoral CD3, CD4 and CD8-positive lymphocytes; Serum pro-inflammatory cytokines and chemokines)
time frame: 3 years
measure: Immune effects with biomarker analyses (Tumor PD-L1 by IHC; Density of peri-tumoral and intra-tumoral CD3, CD4 and CD8-positive lymphocytes; Serum pro-inflammatory cytokines and chemokines)
time frame: 3 years
measure: Toxicities as per NCI CTCAE v4.1
time frame: 3 years
measure: Rate of completion of surgery within the initially planned window as per RECIST v1.1
time frame: 3 years
measure: Rate of disease progression as per RECIST v1.1 during the pre-operative treatment period
time frame: 3 years
measure: Rate of post-operative complications as per NCI CTCAE v4.1
time frame: 3 years
measure: Optimal biologically active dose of mocetinostat (Correlation of tumor and serum-based assessments with mocetinostat dose levels)
time frame: 3 years
measure: Changes in serum mocetinostat concentrations prior to and following durvalumab therapy
time frame: 3 years
measure: Dynamic changes in immune cell activation and/or suppression using flow cytometry and DNA/RNA sequencing (tumor and immune cell genome and trascriptome analysis)
time frame: 3 years
measure: Dynamic changes in intratumoral hypoxia with pre-operative mocetinostat and durvalumab therapy using 18FAZA PET
time frame: 3 years
arm group label: Mocetinostat and Durvalumab
arm group type: Experimental
description: Patients will start therapy with mocetinostat within 10 days of study enrollment. Mocetinostat will be given in 2 dose levels (n = 6 evaluable patients each) of 70mg three-times weekly and 90mg three-times weekly for 2 weeks.
Durvalumab will be given as a single infusion at a dose of 1500mg, over a period of 1-hour, on day 8 of the study.
intervention type: Drug
intervention name: Mocetinostat
description: Mocetinostat (MGCD0103) is a potent small molecule HDAC inhibitor that targets human HDAC isoforms. It is an orally bioavailable, second generation benzamide inhibitor of HDAC 1, 2, 3 and 11 with broad spectrum antitumor activity in vitro and in vivo.
arm group label: Mocetinostat and Durvalumab
other name: MGCD0103
intervention type: Biological
intervention name: Durvalumab
description: Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against human PD-L1. It is selective for recombinant PD-L1 and blocks the binding of recombinant PD-L1 to the PD-1 and CD80 receptors.
arm group label: Mocetinostat and Durvalumab
other name: MEDI4736
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lillian Siu, MD
role: Principal Investigator
affiliation: Staff Physician and Medical Oncologist
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Durvalumab
mesh term: Mocetinostat