Clinical Trials /

Ipilimumab, Nivolumab, and Radiation Therapy in Treating Patients With HPV Positive Advanced Oropharyngeal Squamous Cell Carcinoma

NCT03799445

Description:

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 human papillomavirus (HPV) positive stage oropharyngeal squamous cell carcinoma that has spread to other places in the body. 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.

Related Conditions:
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ipilimumab, Nivolumab, and Radiation Therapy in Treating Patients With HPV Positive Advanced Oropharyngeal Squamous Cell Carcinoma
  • 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 60 Gy in Low-Intermediate Volume, Local-Regionally Advanced HPV-Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Clinical Trial IDs

  • ORG STUDY ID: 2018-0381
  • SECONDARY ID: NCI-2018-03260
  • SECONDARY ID: 2018-0381
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03799445

Conditions

  • CDKN2A-p16 Positive
  • Human Papillomavirus DNA
  • Human Papillomavirus mRNA
  • Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma
  • Oropharyngeal Basaloid Carcinoma
  • Posterior Tongue Squamous Cell Carcinoma
  • Soft Palate Squamous Cell Carcinoma
  • Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7
  • Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7
  • Tonsillar Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (nivolumab, ipilimumab, IMRT)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, ipilimumab, IMRT)

Purpose

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 human papillomavirus (HPV) positive stage oropharyngeal squamous cell carcinoma that has spread to other places in the body. 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.

Detailed Description

      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] or intensity modulated proton therapy [IMPT]).

      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 evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine
      profiles before and after radiation therapy with IMRT versus IMPT.

      IV. 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 courses in
      the absence of disease progression or unacceptable toxicity. Beginning on day 1 of course 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, ipilimumab, IMRT)ExperimentalPatients 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 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of course 2, patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically newly confirmed diagnosis of squamous cell carcinoma
             (including the histological variants of papillary or basaloid) of the oropharynx
             (tonsil, base of tongue, soft palate, or oropharyngeal walls)

          -  Clinical American Joint Committee on Cancer (AJCC) 7th edition stage T1N2a-N2CM0,
             T2N1-N2CM0, T3N0-N2CM0, equivalent to (The International Collaboration on
             Oropharyngeal Cancer Network for Staging [ICON-S]) stage 1 and 2 (T1 N2, T2 N1-N2, T3
             N0-N2) excluding T1N0-N1 and T2N0

          -  Tumor positive for p16 immunohistochemistry (IHC) (defined as greater than 70% strong
             nuclear or nuclear and cytoplasmic staining of tumor cells) and HPV DNA in situ
             hybridization or HPV messenger ribonucleic acid (mRNA) RNAScope. Repeat samples may be
             required if adequate diagnostic tissue is unavailable for testing

          -  Zubrod Performance Status of 0-1

          -  Patients must have radiographically evident measurable disease at the primary site or
             at nodal stations per response evaluation criteria in solid tumors (Response
             Evaluation Criteria in Solid Tumors [RECIST]) 1.1 documented by diagnostic quality CT
             or magnetic resonance imaging (MRI) of the neck with contrast within 28 days prior to
             registration; a FDG-PET/CT of the neck performed for the purposes of radiation
             planning is acceptable as a substitute if the CT is of diagnostic quality

          -  Diagnostic quality cross sectional imaging of the thorax within 28 days prior to
             registration. A 18-FDG-PET/CT or conventional CT are acceptable

          -  FDG-PET/CT of the neck is required within 28 days prior to registration for comparison
             to post treatment FDG-PET/CT

          -  History and physical exam within 1 month prior to registration

          -  Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct
             procedure) by radiation oncologist, medical oncologist or ear, nose, throat (ENT)/head
             and neck surgeons within 45 days prior to registration

          -  Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 2 weeks prior to
             registration)

          -  Platelets >= 100,000 cells/mm^3 (within 2 weeks prior to registration)

          -  Hemoglobin >= 8.0 g/dl; Note: The use of transfusion or other intervention to achieve
             Hgb >= 8.0 g/dl is acceptable (within 2 weeks prior to registration)

          -  Serum creatinine =< 1.5 mg/dl or creatinine clearance (CC) >= 50 ml/min determined by
             24-hour collection or estimated by Cockcroft-Gault formula (within 2 weeks prior to
             registration)

          -  Bilirubin =< 2 mg/dl (within 2 weeks prior to registration)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the upper
             limit of normal (within 2 weeks prior to registration)

          -  Sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg),
             albumin, amylase, lipase, thyroid stimulating hormone (TSH) within 2 weeks prior to
             registration

          -  Negative serum pregnancy test within 2 weeks prior to registration for women of
             childbearing potential

          -  Seronegative for active hepatitis-B or hepatitis-C infection and seronegative for
             human immunodeficiency virus (HIV)

          -  Mandatory submission of hematoxylin and eosin (H&E) and paraffin-embedded tumor block
             or unstained slides

          -  Patients must provide their personal smoking history by use of a computer assisted,
             self-interview (CASI) application. Repeat imaging for variability of within 96 hours
             of this time frame should be allowed to avoid unnecessary re-imaging and its financial
             and potential physical consequences for patients

        Exclusion Criteria:

          -  Cancers of the oral cavity (oral tongue, floor mouth, alveolar ridge, buccal or lip),
             or the nasopharynx, hypopharynx, or larynx, even if p16 positive

          -  Carcinoma of the neck of unknown primary site origin (even if p16 positive)

          -  Definitive clinical or radiologic evidence of metastatic disease or adenopathy below
             the clavicles

          -  Gross total excision of both primary and nodal disease with curative intent; this
             includes tonsillectomy, local excision of primary site, and nodal excision that
             removes all clinically and radiographically evident disease

          -  Simultaneous primary cancers or separate bilateral primary tumor sites

          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
             for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast,
             oral cavity, or cervix are all permissible)

          -  Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
             different cancer is allowable

          -  Prior RT to the region of the study cancer that would result in overlap of radiation
             therapy fields

          -  Severe, active co-morbidity defined as any of the following: Unstable angina and/or
             congestive heart failure requiring hospitalization within the last 6 months; acute
             bacterial or fungal infection requiring intravenous antibiotics at the time of
             registration; chronic obstructive pulmonary disease exacerbation or other respiratory
             illness requiring hospitalization or precluding study therapy within 30 days of
             registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation
             defects; a diagnosis of immunodeficiency or use of any form of systemic
             immunosuppressive therapy. The use of physiologic doses of corticosteroids may be
             approved after consultation with the Sponsor

          -  Active autoimmune disease that has required systemic treatment in past 2 years (i.e.
             with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment. Steroid premedications for contrast allergy allowed

          -  Has evidence of active, non-infectious pneumonitis

          -  Has received a live vaccine within 30 days of planned start of study therapy

          -  Pregnancy or breast-feeding; this exclusion is necessary because the treatment
             involved in this study may be significantly teratogenic

          -  History of severe hypersensitivity or contraindication to CT or PET contrast material
             uncontrolled with pre-medications (steroids, antihistamines)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT) (safety lead-in)
Time Frame:Up to 28 days post-completion of radiation therapy
Safety Issue:
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.

Secondary Outcome Measures

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
Safety Issue:
Description:
Measure:Number of patients who tolerated protocol therapy (safety lead-in)
Time Frame:Up to 12 weeks (end of course 2)
Safety Issue:
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
Safety Issue:
Description:
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)
Safety Issue:
Description:Incidence of adverse events (acute and chronic toxicities) will be assessed per CTCAE Patient Reported Outcome (PRO).
Measure:Acute toxicity profiles (Phase II) assessed by CTCAE v 4.
Time Frame:From start of treatment up to 6 months
Safety Issue:
Description:Will be assessed by CTCAE v 4.
Measure:Number of patients who experience >= grade 3 treatment-related adverse event (Phase II)
Time Frame:From start of treatment up to 6 months
Safety Issue:
Description:
Measure:Toxicity profiles (Phase II) assessed per CTCAE v 4.
Time Frame:At 1 and 2 years
Safety Issue:
Description:Will be assessed per CTCAE v 4.
Measure:Patient-reported swallowing outcomes (Phase II) determined by M. D. Anderson Symptom Inventory - Head & Neck (MDASI-HN)
Time Frame:At 1 and 2 years
Safety Issue:
Description:
Measure:Patterns of failure (local-regional relapse) versus [vs] distant) (Phase II) determined by RECIST 1.1
Time Frame:At 1 and 2 years
Safety Issue:
Description:
Measure:Overall survival (Phase II)
Time Frame:At 1 and 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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