<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/NCT03019003</url>
  </required_header>
  <id_info>
    <org_study_id>16-425</org_study_id>
    <nct_id>NCT03019003</nct_id>
  </id_info>
  <brief_title>Oral Decitabine (ASTX727) and Durvalumab in Recurrent and/or Metastatic Head and Neck Cancer Patients</brief_title>
  <official_title>A Phase IB Rescue Study With Oral Decitabine (AStX727) and Durvalumab (MEDI4736) Combination Therapy in Recurrent and/or Metastatic Head and Neck Cancer Patients Who Have Progressed on Anti-PD-1, Anti-PD-L1, or Anti-CTLA-4 Monotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Astex Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</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 is a non-randomized, open-label, Phase IbI study to assess the safety and efficacy of&#xD;
      oral decitabine (ASTX727) and durvalumab (MEDI4736) combination therapy in the treatment of&#xD;
      patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck&#xD;
      (SCCHN) who have progressed during or after treatment with anti-PD-1, anti-PD-L1, or&#xD;
      anti-CTLA-4 monotherapy for recurrent and/or metastatic disease. The clinical trial is&#xD;
      studying drugs that can boost the participant's immune system against the cancer cells as a&#xD;
      possible treatment for head and neck cancer.&#xD;
&#xD;
      The study interventions involved in this study are:&#xD;
&#xD;
        -  Oral Decitabine (ASTX 727)&#xD;
&#xD;
        -  Durvalumab (MEDI4736)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase I clinical trial, which tests the safety of an investigational&#xD;
      drug and also tries to define the appropriate dose of the investigational drug to use for&#xD;
      further studies. &quot;Investigational&quot; means that the drugs are still being studied.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has not approved durvalumab (MEDI4736) or&#xD;
      tremelimumab as a treatment for any disease.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has not approved oral decitabine (ASTX 7272)&#xD;
      for the participant's specific disease but it has been approved for other uses.&#xD;
&#xD;
      This is a first in human study evaluating the safety of combining these different drugs.&#xD;
      Durvalumab (MEDI4736) is part of a family of proteins that make up the immune system. The&#xD;
      body generates these proteins, or antibodies, in response to foreign substances (particles&#xD;
      not typically found in the body such as bacteria and viruses) and these antibodies can&#xD;
      protect against infection. Durvalumab (MEDI4736) is an antibody that is being studied in&#xD;
      several other clinical trials to see if it has an effect in helping the immune system to&#xD;
      recognize and eliminate abnormal cells in the body.&#xD;
&#xD;
      Investigators hope that decitabine may increase the chance of the immune system to recognize&#xD;
      the cancer cells.&#xD;
&#xD;
      In this research study, the investigators are looking for the highest effective dose of&#xD;
      decitabine in combination with durvalumab (MEDI4736) to improve the natural ability of the&#xD;
      immune system to recognize and target head and neck cancer cells.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 20, 2017</start_date>
  <completion_date type="Anticipated">January 2025</completion_date>
  <primary_completion_date type="Anticipated">July 2023</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>Phase I: Biologically Effective Dose (BED) of oral decitabine (ASTX 727)</measure>
    <time_frame>2 months</time_frame>
    <description>Changes in HLA Class I and tumor antigen expression</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II: Progression free survival (PFS)</measure>
    <time_frame>2 years</time_frame>
    <description>RECIST 1.1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Phase I: Number of participants with treatment-related adverse events</measure>
    <time_frame>2 years</time_frame>
    <description>CTCAE v4.3.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II: Best overall objective response rate (ORR)</measure>
    <time_frame>2 years</time_frame>
    <description>RECIST 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II: Overall survival (OS)</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Head and Neck Cancer</condition>
  <arm_group>
    <arm_group_label>Oral Decitabine and Durvalumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral decitabine (ASTX 727) will be administered alone in Cycle 1 and the combination of oral decitabine and durvalumab therapy will be given in Cycles 2-12.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oral Decitabine</intervention_name>
    <description>Hypomethylating agent</description>
    <arm_group_label>Oral Decitabine and Durvalumab</arm_group_label>
    <other_name>ASTX 727</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>anti-PD-L1</description>
    <arm_group_label>Oral Decitabine and Durvalumab</arm_group_label>
    <other_name>MEDI4736</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent and any locally-required authorization (e.g., HIPAA in the&#xD;
             UEU Data Privacy Directive in the EU) obtained from the subject prior to performing&#xD;
             any protocol-related procedures, including screening evaluations&#xD;
&#xD;
          -  Age ≥ 18 years at time of study entry or adult male or female (according to age of&#xD;
             majority as defined as ≥18 years)&#xD;
&#xD;
          -  Histologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx,&#xD;
             hypopharynx, or larynx) not amenable to therapy with curative intent (surgery or&#xD;
             radiation therapy with or without chemotherapy). Patients who refuse radical resection&#xD;
             are eligible.&#xD;
&#xD;
          -  Tumor progression or recurrence during or after treatment with anti-PD1, anti-PDL1,&#xD;
             anti-PDL2, anti-CTLA4, or other immune checkpoint inhibitor where the most recent dose&#xD;
             was given within 3 months prior to study registration.&#xD;
&#xD;
          -  Must give valid written consent to provide archival FFPE and/or newly acquired tumor&#xD;
             tissue for the purpose of establishing baseline PD-L1 status as well as consent to&#xD;
             provide on- and/or post-treatment tumor biopsy sample.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment&#xD;
&#xD;
          -  Life expectancy of &gt; 6 months&#xD;
&#xD;
          -  At least 1 lesion that can be accurately measured at baseline as &gt; 10 mm in the&#xD;
             longest diameter (except lymph nodes which must have a short axis &gt;15 mm) with CT or&#xD;
             MRI and that is suitable for accurate repeated measurements as per RECIST 1.1&#xD;
             guidelines.&#xD;
&#xD;
          -  Adequate normal organ and marrow function as defined below (within 28 days prior to&#xD;
             study registration):&#xD;
&#xD;
               -  Hemoglobin ≥ 9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (&gt; 1500 per mm3)&#xD;
&#xD;
               -  Platelet count ≥ 100 x 109/L (&gt;100,000 per mm3)&#xD;
&#xD;
               -  Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not&#xD;
                  apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent&#xD;
                  hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis&#xD;
                  or hepatic pathology), who will be allowed only in consultation with their&#xD;
                  physician.&#xD;
&#xD;
               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver&#xD;
                  metastases are present, in which case it must be ≤ 5x ULN&#xD;
&#xD;
               -  Serum creatinine level &lt;1.5 x ULN and CL&gt;40 mL/min by the Cockcroft-Gault formula&#xD;
                  (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of&#xD;
                  creatinine clearance:&#xD;
&#xD;
        Males:&#xD;
&#xD;
        --Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)&#xD;
&#xD;
        Females:&#xD;
&#xD;
        --Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)&#xD;
&#xD;
          -  Female subjects must either be of non-reproductive potential (ie, post-menopausal by&#xD;
             history: ≥60 years old and no menses for ≥1 year without an alternative medical cause;&#xD;
             OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of&#xD;
             bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.&#xD;
&#xD;
          -  Male subjects with a female partner of childbearing potential must commit to true&#xD;
             abstinence from heterosexual contact or commit to the use of male condom plus&#xD;
             spermicide throughout the course of the study, and avoid fathering a child during the&#xD;
             course of the study (including dose interruptions) and for 6 months following the last&#xD;
             dose of azacitidine.&#xD;
&#xD;
          -  All men and women of childbearing potential must use acceptable methods of birth&#xD;
             control throughout the study as described below:&#xD;
&#xD;
        Females of childbearing potential: Recommendation is for at least one highly effective&#xD;
        contraceptive methods during the study and must agree to continue using such precautions&#xD;
        for 180 days after the last dose of investigational product.&#xD;
&#xD;
        Non-sterilized males : Non-sterilized male patients who are sexually active with a female&#xD;
        partner of childbearing potential must use male condom plus spermicide from screening&#xD;
        through 180 days after the last dose of investigational product.&#xD;
&#xD;
        -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 follo&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff&#xD;
             and/or staff at the study site)&#xD;
&#xD;
          -  Histologically confirmed squamous cell carcinoma of any other primary anatomic&#xD;
             location in the head and neck (eg. paranasal cavity) and non-squamous histologies (eg.&#xD;
             nasopharynx or salivary gland)&#xD;
&#xD;
          -  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 eg, cervical&#xD;
                  cancer in situ&#xD;
&#xD;
          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,&#xD;
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal&#xD;
             antibodies, other investigational agent) ≤ 21days prior to the first dose of study&#xD;
             drug&#xD;
&#xD;
          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3&#xD;
             electrocardiograms (ECGs) using Fredericia's Correction&#xD;
&#xD;
          -  Current or prior use of immunosuppressive medication within 28 days before the first&#xD;
             dose of durvalumab (MEDI4736) or tremelimumab, with the exceptions of intranasal and&#xD;
             inhaled corticosteroids or systemic corticosteroids at physiological doses, which are&#xD;
             not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid&#xD;
&#xD;
          -  Any unresolved toxicity NCI CTCAE grade 2 from previous anti-cancer therapy with the&#xD;
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion&#xD;
             criteria.&#xD;
&#xD;
          -  Patients with Grade &gt; 2 neuropathy will be evaluated on a case-by-case basis and may&#xD;
             be included after consultation with the Study Physician.&#xD;
&#xD;
             --Patients with irreversible toxicity not reasonably expected to be exacerbated by&#xD;
             treatment with their assigned IP (eg, hearing loss) may be included after consultation&#xD;
             with the Study Physician.&#xD;
&#xD;
          -  Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous&#xD;
             immunotherapy agent, or any unresolved irAE &gt;Grade 1&#xD;
&#xD;
          -  Abnormal coagulation parameters (PT &gt;15 seconds, PTT&gt;40 seconds, and/or INR &gt;1.5)&#xD;
&#xD;
          -  Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects&#xD;
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within&#xD;
             the past 2 years) are not excluded.&#xD;
&#xD;
          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,&#xD;
             ulcerative colitis)&#xD;
&#xD;
          -  History of primary immunodeficiency&#xD;
&#xD;
          -  History of allogeneic organ transplant&#xD;
&#xD;
          -  History of hypersensitivity to durvalumab (MEDI4736), tremelimumab, or any excipient&#xD;
&#xD;
          -  Known or suspected hypersensitivity to azacitidine or mannitol&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable&#xD;
             angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months,&#xD;
             active peptic ulcer disease or gastritis, active bleeding diatheses including any&#xD;
             subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human&#xD;
             immunodeficiency virus (HIV), or psychiatric illness/social situations that would&#xD;
             limit compliance with study requirements or compromise the ability of the subject to&#xD;
             give written informed consent&#xD;
&#xD;
          -  Known history of previous clinical diagnosis of tuberculosis&#xD;
&#xD;
          -  Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing&#xD;
             signs/symptoms related to the infection without improvement despite appropriate&#xD;
             antibiotics, antiviral therapy and/or other treatment)&#xD;
&#xD;
          -  History of leptomeningeal carcinomatosis&#xD;
&#xD;
          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within&#xD;
             30 days of receiving durvalumab (MEDI4736) or tremelimumab&#xD;
&#xD;
          -  Female subjects who are pregnant, breast-feeding or male or female patients of&#xD;
             reproductive potential who are not employing an effective method of birth control&#xD;
&#xD;
          -  Any condition that, in the opinion of the investigator, would interfere with&#xD;
             evaluation of study treatment or interpretation of patient safety or study results&#xD;
&#xD;
          -  Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive&#xD;
             of but not limited to surgery, radiation and/or corticosteroids.&#xD;
&#xD;
          -  Subjects with uncontrolled seizures.&#xD;
&#xD;
          -  Female patients who are pregnant or breastfeeding or male or female patients of&#xD;
             reproductive potential who are not willing to employ effective birth control from&#xD;
             screening to 180 days after the last dose of azacitidine, durvalumab (MEDI4736) and/or&#xD;
             tremelimumab therapy. Lactating females must agree not to breast feed throughout this&#xD;
             period&#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>Sara Pai, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 6, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>February 17, 2023</last_update_submitted>
  <last_update_submitted_qc>February 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Sara Pai, MD, PhD</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Head and Neck Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Head and Neck Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Decitabine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03019003
org study id: 16-425
nct id: NCT03019003
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a non-randomized, open-label, Phase IbI study to assess the safety and efficacy of
      oral decitabine (ASTX727) and durvalumab (MEDI4736) combination therapy in the treatment of
      patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck
      (SCCHN) who have progressed during or after treatment with anti-PD-1, anti-PD-L1, or
      anti-CTLA-4 monotherapy for recurrent and/or metastatic disease. The clinical trial is
      studying drugs that can boost the participant's immune system against the cancer cells as a
      possible treatment for head and neck cancer.

      The study interventions involved in this study are:

        -  Oral Decitabine (ASTX 727)

        -  Durvalumab (MEDI4736)
This research study is a Phase I clinical trial, which tests the safety of an investigational
      drug and also tries to define the appropriate dose of the investigational drug to use for
      further studies. "Investigational" means that the drugs are still being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved durvalumab (MEDI4736) or
      tremelimumab as a treatment for any disease.

      The FDA (the U.S. Food and Drug Administration) has not approved oral decitabine (ASTX 7272)
      for the participant's specific disease but it has been approved for other uses.

      This is a first in human study evaluating the safety of combining these different drugs.
      Durvalumab (MEDI4736) is part of a family of proteins that make up the immune system. The
      body generates these proteins, or antibodies, in response to foreign substances (particles
      not typically found in the body such as bacteria and viruses) and these antibodies can
      protect against infection. Durvalumab (MEDI4736) is an antibody that is being studied in
      several other clinical trials to see if it has an effect in helping the immune system to
      recognize and eliminate abnormal cells in the body.

      Investigators hope that decitabine may increase the chance of the immune system to recognize
      the cancer cells.

      In this research study, the investigators are looking for the highest effective dose of
      decitabine in combination with durvalumab (MEDI4736) to improve the natural ability of the
      immune system to recognize and target head and neck cancer cells.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase I: Biologically Effective Dose (BED) of oral decitabine (ASTX 727)
time frame: 2 months
description: Changes in HLA Class I and tumor antigen expression
measure: Phase II: Progression free survival (PFS)
time frame: 2 years
description: RECIST 1.1
measure: Phase I: Number of participants with treatment-related adverse events
time frame: 2 years
description: CTCAE v4.3.
measure: Phase II: Best overall objective response rate (ORR)
time frame: 2 years
description: RECIST 1.1.
measure: Phase II: Overall survival (OS)
time frame: 2 years
arm group label: Oral Decitabine and Durvalumab
arm group type: Experimental
description: Oral decitabine (ASTX 727) will be administered alone in Cycle 1 and the combination of oral decitabine and durvalumab therapy will be given in Cycles 2-12.
intervention type: Drug
intervention name: Oral Decitabine
description: Hypomethylating agent
arm group label: Oral Decitabine and Durvalumab
other name: ASTX 727
intervention type: Drug
intervention name: Durvalumab
description: anti-PD-L1
arm group label: Oral Decitabine and Durvalumab
other name: MEDI4736
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sara Pai, MD, PhD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Sara Pai, MD, PhD
investigator title: MD, PhD
mesh term: Head and Neck Neoplasms
mesh term: Durvalumab
mesh term: Decitabine
sharing ipd: No