<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/NCT03799445</url>
  </required_header>
  <id_info>
    <org_study_id>2018-0381</org_study_id>
    <secondary_id>NCI-2018-03260</secondary_id>
    <secondary_id>2018-0381</secondary_id>
    <nct_id>NCT03799445</nct_id>
  </id_info>
  <brief_title>Ipilimumab, Nivolumab, and Radiation Therapy in Treating Patients With HPV Positive Advanced Oropharyngeal Squamous Cell Carcinoma</brief_title>
  <official_title>Phase 2 Study (With Safety Lead in) of the Safety, Tolerability and Efficacy of Anti-CTLA4 (Ipilimumab) and Anti-PD-1 (Nivolumab) in Combination With Radiation Therapy to 50-66 Gy in Low-Intermediate Volume, Local-Regionally Advanced HPV-Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>M.D. Anderson Cancer Center</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies the side effects and best dose of ipilimumab, nivolumab, and&#xD;
      radiation therapy and how well they work in treating patients with advanced human&#xD;
      papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Immunotherapy with&#xD;
      monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system&#xD;
      attack the cancer, and may interfere with the ability of tumor cells to grow and spread.&#xD;
      Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving&#xD;
      ipilimumab, nivolumab, and radiation therapy may work better in treating patients with HPV&#xD;
      positive oropharyngeal squamous cell carcinoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the safety, tolerability and feasibility of ipilimumab and nivolumab when&#xD;
      administered concurrently with reduced-field radiotherapy (intensity-modulated radiation&#xD;
      therapy [IMRT]).&#xD;
&#xD;
      II. To evaluate the clinical complete response rate to ipilimumab, nivolumab and IMRT with&#xD;
      reduced field at six months as indicated by fluorodeoxyglucose - positron emission&#xD;
      tomography/computed tomography (FDG-PET/CT) post completion of radiation therapy (RT).&#xD;
&#xD;
      III. To evaluate the 2-year progression-free survival (PFS) rate of subjects with&#xD;
      low-intermediate volume, local-regionally advanced, human papilloma virus (HPV)-positive&#xD;
      squamous cell carcinoma of the head and neck (SCCHN) treated with ipilimumab, nivolumab and&#xD;
      reduced-field IMRT.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate overall response rate to six weeks of induction immunotherapy (IO).&#xD;
&#xD;
      II. To evaluate the frequency of pharyngeal dysphasia as measured by Dynamic Imaging (Dynamic&#xD;
      Imaging Grade of Swallowing Toxicity [DIGEST]) grade on modified barium swallow (MBS) and&#xD;
      patient-reported symptoms (MD Anderson Dysphagia Inventory [MDADI]) at 6 month, 1 and 2 years&#xD;
      after radiotherapy ([IMRT].&#xD;
&#xD;
      III. To measure acute and chronic toxicities per Patient-Reported Outcomes Common Terminology&#xD;
      Criteria for Adverse Events (CTCAE PRO).&#xD;
&#xD;
      IV. To measure acute toxicity profiles at the end of radiation therapy and IO and at 6&#xD;
      months.&#xD;
&#xD;
      V. To measure late toxicity profiles at 1 and 2 years. VI. To determine local and regional&#xD;
      control at 6 and 12 months. VII. To determine patterns of failure (local-regional relapse vs.&#xD;
      distant) at 1 and 2 years.&#xD;
&#xD;
      VIII. To determine overall survival (OS) at 1 and 2 years.&#xD;
&#xD;
      CORRELATIVE OBJECTIVES:&#xD;
&#xD;
      I. To evaluate associations between total mutational load, interferon (INF) gamma score, T&#xD;
      cell clonality at diagnosis with clinical response to induction, combination CTLA-4 PD-1&#xD;
      checkpoint blockade.&#xD;
&#xD;
      II. To evaluate changes in the tumor immune microenvironment (CD8 + INF gamma score, T cell&#xD;
      clonality, in tumor biopsy specimens pre and post induction immunotherapy (IO).&#xD;
&#xD;
      III. To evaluate dynamic changes in and clearance of oral HPV and cell-free deoxyribonucleic&#xD;
      acid (cfDNA) viral load during therapy and to investigate associations with PFS and OS.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine profiles&#xD;
      before and after induction IO.&#xD;
&#xD;
      II. To evaluate changes in the T cell receptor repertoire in tumor-infiltrating lymphocyte&#xD;
      (TIL) and the peripheral blood in tumor biopsy specimens pre and post induction IO.&#xD;
&#xD;
      III. To determine the negative and positive predictive values (NPV and PPV) of FDG-PET/CT&#xD;
      12-14 weeks after end of RT for 1 year and 2 year PFS and OS.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and&#xD;
      ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 cycles in&#xD;
      the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 2,&#xD;
      patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of&#xD;
      disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 2 weeks, every 3 months for&#xD;
      2 years, every 6 months for 3 years, and then annually thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 25, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <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>Dose limiting toxicity (DLT) (safety lead-in)</measure>
    <time_frame>Up to 28 days post-completion of radiation therapy</time_frame>
    <description>Defined as any &gt;= grade 3 adverse event (Common Terminology Criteria for Adverse Events [CTCAE], version [v.] 4) that is related to immunotherapy (IO) that does not resolve to grade 1 or less within 28 days.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complete response rate (Phase II)</measure>
    <time_frame>At 6 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression-free survival (PFS) (Phase II)</measure>
    <time_frame>From start of therapy to progression or disease or death from any cause, assessed up to 2 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients who experience a &gt;= grade 3 treatment-related adverse event (safety lead-in)</measure>
    <time_frame>Up to 28 days post-completion of radiation therapy</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who tolerated protocol therapy (safety lead-in)</measure>
    <time_frame>Up to 12 weeks (end of cycle 2)</time_frame>
    <description>The number of patients who tolerated protocol therapy, including completion of radiotherapy without a treatment break and who were administered immunotherapy (IO) will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who achieve a clinical complete response (safety lead-in)</measure>
    <time_frame>Up to 28 weeks after radiation therapy</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute and chronic adverse events (Phase II)</measure>
    <time_frame>Up to 3 months from the end of intensity-modulated radiation therapy (IMRT)</time_frame>
    <description>Incidence of adverse events (acute and chronic toxicities) will be assessed per CTCAE Patient Reported Outcome (PRO).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute toxicity profiles (Phase II)</measure>
    <time_frame>At the end of radiation therapy, end of IO, and 6 months</time_frame>
    <description>Will be assessed by CTCAE v 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who experience &gt;= grade 3 treatment-related adverse event (Phase II)</measure>
    <time_frame>At the end of radiation therapy, end of IO, and 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Late toxicity profiles (Phase II)</measure>
    <time_frame>At 1 and 2 years</time_frame>
    <description>Will be assessed per CTCAE v 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported swallowing outcomes (Phase II)</measure>
    <time_frame>At 1 and 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patterns of failure (local-regional relapse versus [vs] distant) (Phase II)</measure>
    <time_frame>At 1 and 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (Phase II)</measure>
    <time_frame>At 1 and 2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">180</enrollment>
  <condition>Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8</condition>
  <condition>Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8</condition>
  <condition>Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma</condition>
  <condition>Oropharyngeal Basaloid Carcinoma</condition>
  <condition>Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8</condition>
  <condition>Posterior Tongue Squamous Cell Carcinoma</condition>
  <condition>Soft Palate Squamous Cell Carcinoma</condition>
  <condition>Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7</condition>
  <condition>Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7</condition>
  <condition>Tonsillar Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment (nivolumab, ipilimumab, IMRT)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 2, patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Intensity-Modulated Radiation Therapy</intervention_name>
    <description>Undergo IMRT</description>
    <arm_group_label>Treatment (nivolumab, ipilimumab, IMRT)</arm_group_label>
    <other_name>IMRT</other_name>
    <other_name>Intensity Modulated RT</other_name>
    <other_name>Intensity-Modulated Radiotherapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, ipilimumab, IMRT)</arm_group_label>
    <other_name>Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody</other_name>
    <other_name>BMS-734016</other_name>
    <other_name>MDX-010</other_name>
    <other_name>MDX-CTLA4</other_name>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, ipilimumab, IMRT)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (nivolumab, ipilimumab, IMRT)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Questionnaire Administration</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (nivolumab, ipilimumab, IMRT)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically newly confirmed diagnosis of squamous cell carcinoma&#xD;
             (including the histological variants of papillary or basaloid) of the oropharynx&#xD;
             (tonsil, base of tongue, soft palate, or oropharyngeal walls)&#xD;
&#xD;
          -  Clinical American Joint Committee on Cancer (AJCC) 7th edition stage T1N2a-N2CM0,&#xD;
             T2N1-N2CM0, T3N0-N2CM0, equivalent to AJCC 8th edition stage 1 and 2 (T1 N2, T2 N1-N2,&#xD;
             T3 N0-N2) excluding T1N0-N1 and T2N0 (Brian O'Sullivan et al. 2016)&#xD;
&#xD;
          -  Tumor positive for p16 immunohistochemistry (IHC) (defined as greater than 70% strong&#xD;
             nuclear or nuclear and cytoplasmic staining of tumor cells) and HPV DNA in situ&#xD;
             hybridization or HPV messenger ribonucleic acid (mRNA) RNAScope. Repeat samples may be&#xD;
             required if adequate diagnostic tissue is unavailable for testing&#xD;
&#xD;
          -  Zubrod Performance Status of 0-1&#xD;
&#xD;
          -  Patients must have radiographically evident measurable disease at the primary site or&#xD;
             at nodal stations per response evaluation criteria in solid tumors (Response&#xD;
             Evaluation Criteria in Solid Tumors [RECIST]) 1.1 documented by diagnostic quality CT&#xD;
             or magnetic resonance imaging (MRI) of the neck with contrast within 28 days prior to&#xD;
             registration; a FDG-PET/CT of the neck performed for the purposes of radiation&#xD;
             planning is acceptable as a substitute if the CT is of diagnostic quality&#xD;
&#xD;
          -  Diagnostic quality cross sectional imaging of the thorax within 28 days prior to&#xD;
             registration. A 18-FDG-PET/CT or conventional CT are acceptable&#xD;
&#xD;
          -  FDG-PET/CT of the neck is required within 28 days prior to registration for comparison&#xD;
             to post treatment FDG-PET/CT. Note: Repeat imaging for variability within 96 hours of&#xD;
             this time frame should be allowed to avoid unnecessary re-imaging and its financial&#xD;
             and potential physical consequences for patients&#xD;
&#xD;
          -  History and physical exam within 1 month prior to registration&#xD;
&#xD;
          -  Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct&#xD;
             procedure) by radiation oncologist, medical oncologist or ear, nose, throat (ENT)/head&#xD;
             and neck surgeons within 28 days prior to registration&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,500 cells/mm^3 (within 2 weeks prior to&#xD;
             registration)&#xD;
&#xD;
          -  Platelets &gt;= 100,000 cells/mm^3 (within 2 weeks prior to registration)&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.0 g/dl (within 2 weeks prior to registration); Note: The use of&#xD;
             transfusion or other intervention to achieve Hgb &gt;= 8.0 g/dl is acceptable&#xD;
&#xD;
          -  Serum creatinine &lt; 1.5 mg/dl or creatinine clearance (CC) &gt;= 50 ml/min determined by&#xD;
             24-hour collection or estimated by Cockcroft-Gault formula (within 2 weeks prior to&#xD;
             registration)&#xD;
&#xD;
          -  Bilirubin &lt; 2 mg/dl (within 2 weeks prior to registration)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) &lt; 3 x the upper&#xD;
             limit of normal (within 2 weeks prior to registration)&#xD;
&#xD;
          -  Sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg),&#xD;
             albumin, amylase, lipase, thyroid stimulating hormone (TSH) within 2 weeks prior to&#xD;
             registration&#xD;
&#xD;
          -  Negative serum pregnancy test within 2 weeks prior to registration for women of&#xD;
             childbearing potential&#xD;
&#xD;
          -  Seronegative for active hepatitis-B or hepatitis-C infection and seronegative for&#xD;
             human immunodeficiency virus (HIV)&#xD;
&#xD;
          -  Mandatory submission of hematoxylin and eosin (H&amp;E) and paraffin-embedded tumor block&#xD;
             or unstained slides&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cancers of the oral cavity (oral tongue, floor mouth, alveolar ridge, buccal or lip),&#xD;
             or the nasopharynx, hypopharynx, or larynx, even if p16 positive&#xD;
&#xD;
          -  Carcinoma of the neck of unknown primary site origin (even if p16 positive)&#xD;
&#xD;
          -  Definitive clinical or radiologic evidence of metastatic disease or adenopathy below&#xD;
             the clavicles&#xD;
&#xD;
          -  Gross total excision of both primary and nodal disease with curative intent; this&#xD;
             includes tonsillectomy, local excision of primary site, and nodal excision that&#xD;
             removes all clinically and radiographically evident disease&#xD;
&#xD;
          -  Simultaneous primary cancers or separate bilateral primary tumor sites&#xD;
&#xD;
          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free&#xD;
             for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast,&#xD;
             oral cavity, or cervix are all permissible)&#xD;
&#xD;
          -  Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a&#xD;
             different cancer is allowable; patients who have received PD-1/PD-L1 or CTLA4 therapy&#xD;
             for a previous malignancy are not eligible&#xD;
&#xD;
          -  Prior RT to the region of the study cancer that would result in overlap of radiation&#xD;
             therapy fields&#xD;
&#xD;
          -  Severe, active co-morbidity defined as any of the following: Unstable angina and/or&#xD;
             congestive heart failure requiring hospitalization within the last 6 months; acute&#xD;
             bacterial or fungal infection requiring intravenous antibiotics at the time of&#xD;
             registration; chronic obstructive pulmonary disease exacerbation or other respiratory&#xD;
             illness requiring hospitalization or precluding study therapy within 30 days of&#xD;
             registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation&#xD;
             defects; a diagnosis of immunodeficiency or use of any form of systemic&#xD;
             immunosuppressive therapy. The use of physiologic doses of corticosteroids may be&#xD;
             approved after consultation with the sponsor&#xD;
&#xD;
          -  Active autoimmune disease that has required systemic treatment in past 2 years (i.e.&#xD;
             with use of disease modifying agents, corticosteroids or immunosuppressive drugs).&#xD;
             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment. Steroid premedications for contrast allergy allowed&#xD;
&#xD;
          -  Has evidence of active, non-infectious pneumonitis&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy&#xD;
&#xD;
          -  Pregnancy or breast-feeding; this exclusion is necessary because the treatment&#xD;
             involved in this study may be significantly teratogenic&#xD;
&#xD;
          -  History of severe hypersensitivity or contraindication to CT or PET contrast material&#xD;
             uncontrolled with pre-medications (steroids, antihistamines)&#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>Maura L Gillison</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maura Gillison</last_name>
    <phone>713-792-6363</phone>
    <email>mgillison@mdanderson.org</email>
  </overall_contact>
  <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>
    <status>Recruiting</status>
    <contact>
      <last_name>Maura L. Gillison</last_name>
      <phone>713-792-6363</phone>
    </contact>
    <investigator>
      <last_name>Maura L. Gillison</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>MD Anderson Cancer Center Website</description>
  </link>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 13, 2018</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 10, 2019</study_first_posted>
  <last_update_submitted>August 23, 2023</last_update_submitted>
  <last_update_submitted_qc>August 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
    <mesh_term>Oropharyngeal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</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/NCT03799445
org study id: 2018-0381
secondary id: NCI-2018-03260
secondary id: 2018-0381
nct id: NCT03799445
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies the side effects and best dose of ipilimumab, nivolumab, and
      radiation therapy and how well they work in treating patients with advanced human
      papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Immunotherapy with
      monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system
      attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
      Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving
      ipilimumab, nivolumab, and radiation therapy may work better in treating patients with HPV
      positive oropharyngeal squamous cell carcinoma.
PRIMARY OBJECTIVES:

      I. To evaluate the safety, tolerability and feasibility of ipilimumab and nivolumab when
      administered concurrently with reduced-field radiotherapy (intensity-modulated radiation
      therapy [IMRT]).

      II. To evaluate the clinical complete response rate to ipilimumab, nivolumab and IMRT with
      reduced field at six months as indicated by fluorodeoxyglucose - positron emission
      tomography/computed tomography (FDG-PET/CT) post completion of radiation therapy (RT).

      III. To evaluate the 2-year progression-free survival (PFS) rate of subjects with
      low-intermediate volume, local-regionally advanced, human papilloma virus (HPV)-positive
      squamous cell carcinoma of the head and neck (SCCHN) treated with ipilimumab, nivolumab and
      reduced-field IMRT.

      SECONDARY OBJECTIVES:

      I. To evaluate overall response rate to six weeks of induction immunotherapy (IO).

      II. To evaluate the frequency of pharyngeal dysphasia as measured by Dynamic Imaging (Dynamic
      Imaging Grade of Swallowing Toxicity [DIGEST]) grade on modified barium swallow (MBS) and
      patient-reported symptoms (MD Anderson Dysphagia Inventory [MDADI]) at 6 month, 1 and 2 years
      after radiotherapy ([IMRT].

      III. To measure acute and chronic toxicities per Patient-Reported Outcomes Common Terminology
      Criteria for Adverse Events (CTCAE PRO).

      IV. To measure acute toxicity profiles at the end of radiation therapy and IO and at 6
      months.

      V. To measure late toxicity profiles at 1 and 2 years. VI. To determine local and regional
      control at 6 and 12 months. VII. To determine patterns of failure (local-regional relapse vs.
      distant) at 1 and 2 years.

      VIII. To determine overall survival (OS) at 1 and 2 years.

      CORRELATIVE OBJECTIVES:

      I. To evaluate associations between total mutational load, interferon (INF) gamma score, T
      cell clonality at diagnosis with clinical response to induction, combination CTLA-4 PD-1
      checkpoint blockade.

      II. To evaluate changes in the tumor immune microenvironment (CD8 + INF gamma score, T cell
      clonality, in tumor biopsy specimens pre and post induction immunotherapy (IO).

      III. To evaluate dynamic changes in and clearance of oral HPV and cell-free deoxyribonucleic
      acid (cfDNA) viral load during therapy and to investigate associations with PFS and OS.

      EXPLORATORY OBJECTIVES:

      I. To evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine profiles
      before and after induction IO.

      II. To evaluate changes in the T cell receptor repertoire in tumor-infiltrating lymphocyte
      (TIL) and the peripheral blood in tumor biopsy specimens pre and post induction IO.

      III. To determine the negative and positive predictive values (NPV and PPV) of FDG-PET/CT
      12-14 weeks after end of RT for 1 year and 2 year PFS and OS.

      OUTLINE:

      Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and
      ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 cycles in
      the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 2,
      patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 2 weeks, every 3 months for
      2 years, every 6 months for 3 years, and then annually thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose limiting toxicity (DLT) (safety lead-in)
time frame: Up to 28 days post-completion of radiation therapy
description: Defined as any >= grade 3 adverse event (Common Terminology Criteria for Adverse Events [CTCAE], version [v.] 4) that is related to immunotherapy (IO) that does not resolve to grade 1 or less within 28 days.
measure: Complete response rate (Phase II)
time frame: At 6 months
measure: Progression-free survival (PFS) (Phase II)
time frame: From start of therapy to progression or disease or death from any cause, assessed up to 2 years
measure: Number of patients who experience a >= grade 3 treatment-related adverse event (safety lead-in)
time frame: Up to 28 days post-completion of radiation therapy
measure: Number of patients who tolerated protocol therapy (safety lead-in)
time frame: Up to 12 weeks (end of cycle 2)
description: The number of patients who tolerated protocol therapy, including completion of radiotherapy without a treatment break and who were administered immunotherapy (IO) will be assessed.
measure: Number of patients who achieve a clinical complete response (safety lead-in)
time frame: Up to 28 weeks after radiation therapy
measure: Incidence of acute and chronic adverse events (Phase II)
time frame: Up to 3 months from the end of intensity-modulated radiation therapy (IMRT)
description: Incidence of adverse events (acute and chronic toxicities) will be assessed per CTCAE Patient Reported Outcome (PRO).
measure: Acute toxicity profiles (Phase II)
time frame: At the end of radiation therapy, end of IO, and 6 months
description: Will be assessed by CTCAE v 4.
measure: Number of patients who experience >= grade 3 treatment-related adverse event (Phase II)
time frame: At the end of radiation therapy, end of IO, and 6 months
measure: Late toxicity profiles (Phase II)
time frame: At 1 and 2 years
description: Will be assessed per CTCAE v 4.
measure: Patient-reported swallowing outcomes (Phase II)
time frame: At 1 and 2 years
measure: Patterns of failure (local-regional relapse versus [vs] distant) (Phase II)
time frame: At 1 and 2 years
measure: Overall survival (Phase II)
time frame: At 1 and 2 years
arm group label: Treatment (nivolumab, ipilimumab, IMRT)
arm group type: Experimental
description: Patients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 2, patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.
intervention type: Radiation
intervention name: Intensity-Modulated Radiation Therapy
description: Undergo IMRT
arm group label: Treatment (nivolumab, ipilimumab, IMRT)
other name: IMRT
other name: Intensity Modulated RT
other name: Intensity-Modulated Radiotherapy
intervention type: Biological
intervention name: Ipilimumab
description: Given IV
arm group label: Treatment (nivolumab, ipilimumab, IMRT)
other name: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
other name: BMS-734016
other name: MDX-010
other name: MDX-CTLA4
other name: Yervoy
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Treatment (nivolumab, ipilimumab, IMRT)
other name: BMS-936558
other name: MDX-1106
other name: NIVO
other name: ONO-4538
other name: Opdivo
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Treatment (nivolumab, ipilimumab, IMRT)
other name: Quality of Life Assessment
intervention type: Other
intervention name: Questionnaire Administration
description: Ancillary studies
arm group label: Treatment (nivolumab, ipilimumab, IMRT)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Maura L Gillison
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
last name: Maura Gillison
phone: 713-792-6363
email: mgillison@mdanderson.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
url: http://www.mdanderson.org
description: MD Anderson Cancer Center Website
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Oropharyngeal Neoplasms
mesh term: Nivolumab
mesh term: Ipilimumab