Clinical Trial 20274

• Overview

  Study Title:

  A Phase II/III Randomized Study of Maintenance Nivolumab versus Observation in Patients with Locally Advanced, Intermediate Risk HPV Positive OPCA

  Summary:

  This phase II/III trials studies whether maintenance immunotherapy (nivolumab) following definitive treatment with radiation and chemotherapy (cisplatin) result in significant improvement in overall survival (time being alive) and progression-free survival (time being alive without cancer) for patients with intermediate risk human papillomavirus (HPV) positive oropharynx cancer that has spread to nearby tissue or lymph nodes. Drugs used in chemotherapy such as cisplatin work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether chemotherapy and radiation therapy followed by maintenance nivolumab therapy works better than chemotherapy and radiation therapy alone in treating patients with HPV positive oropharyngeal cancer.

  Objective:

  Primary Objective for Phase 2: To assess the efficacy of concurrent definitive therapy followed by nivolumab compared with concurrent definitive therapy followed by observation in terms of progression-free survival (PFS). Primary Objective for Phase 3: To assess the efficacy of concurrent definitive therapy followed by nivolumab compared with concurrent definitive therapy followed by observation in terms of overall survival (OS). Secondary Objectives: To further assess the efficacy of nivolumab compared with observation in terms of: The relationship of baseline PD-L1 expression to clinical outcome. To evaluate the predictive value of HPV16 E6 and E7 DNA in saliva and plasma, at baseline, 12 weeks and 9 months after completion of radiation on PFS and OS in both arms of the study. To evaluate the tumor mutation burden by whole exome sequencing of the initial pretreatment tissue sample as well as samples obtained at the time of progression. To evaluate the association of 12 week post therapy FDG PET/CT with PFS and OS. To establish the prognostic value of SUVmax of primary tumor or neck nodal metastasis of baseline FDG PET/CT for OS (and/or PFS). To correlate SUVmax of primary tumor or nodal metastasis of baseline FDG PET/CT with PD-L1 expression (positive vs. negative). To correlate the post therapy (cisplatin + RT) FDG PET/CT with saliva or plasma levels of HPV DNA collected at the time of the standard 3 months PET/CT scan as well as 6 months later (i.e. 9 months post therapy) for both the observation and Nivolumab groups. To compare the PET based therapy response assessment(Hopkins criteria) to the RECIST 1.1 assessment at 12 week post chemoradiation therapy, for patients who have a PET/CT scan at 12 weeks.

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy; Radiotherapy

  Medications:

  BMS-936558 (Nivolumab); Nivolumab (Opdivo); Radiotherapy (); cisplatin ()

• Inclusion Criteria

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Participants must have oropharynx cancer that is p16-positive by immunohistochemistry with the following criteria: >= 10 pack-years, stage T1-2N2-N3 or T3-4N0-3 OR > Absolute neutrophil count (ANC) >= 1500/mm^3 (must be obtained => Hemoglobin (Hgb) >= 8.0 g/dL (must be obtained => Platelet count >= 100,000/mm^3 (must be obtained => Creatinine clearance of >= 60 ml/min (must be obtained => Total bilirubin within 1.5 times the normal limits (must be obtained => Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) within 2.0 times the normal limits (must be obtained => Alkaline phosphatase within 1.5 times the normal limits (must be obtained =>All women of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy.
  • Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP.
  • Participants must have measurable disease as defined.
  • Participants must have tumor measurements with CT of neck and CT of chest (or CT of neck and FDG PET/CT if standard of care) within 4 weeks prior to Step 1 randomization.
  • Participants must have progression per RECIST criteria AND tissue-proven progression on Arm B treatment within 12 months after completion of radiation therapy.
  • ECOG performance status of 0 or 1.
  • Participants must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition.
  • Participants must not have received non-protocol anti-cancer therapy after completion of radiation and chemotherapy.
  • ANC >= 1500/mm^3 (must be obtained => Hgb >= 8.0 g/dL (must be obtained => Platelet count >= 100,000/mm^3 (must be obtained => Creatinine clearance of >= 60 ml/min (must be obtained => Total bilirubin within 1.5 times the normal limits (must be obtained => SGOT (AST) or SGPT (ALT) within 2.0 times the normal limits (must be obtained => Alkaline phosphatase within 1.5 times the normal limits (must be obtained => Patients must not be pregnant or breast-feeding as chemotherapy, radiation, and immunotherapy may have possible teratogenicity effects; in addition, complications from pregnancy may interfere with the ability of Participants to have an uninterrupted therapy.
  • Participants must have measurable disease.
  • Participants must have tumor measurements with CT of neck and CT of chest (or CT of neck and FDG PET/CT if standard of care) within 4 weeks prior to Step 2 registration.

• Exclusion Criteria

  > Participants must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition.
  • Additional exclusions apply
  • Participants with a history of allergic reactions attributed to platinum-based chemotherapy agents are excluded.
  • Participants must not have had prior systemic therapy, radiation treatment or surgery for p16 positive oropharyngeal squamous cell carcinoma (OPSCC).
  • Participants must not have received previous irradiation for head and neck tumor, skull base, or brain tumors.
  • Participants must not receive investigational agents within 4 weeks of enrollment or at any time while on study.
  • Participants with evidence of distant metastases or leptomeningeal disease (LMD) are excluded.
  • Participants with uncontrolled inter-current illnesses which in the opinion of the investigator will interfere with the ability to undergo therapy including chemotherapy are excluded.
  • Participants with a history of prior or second malignancy are excluded, with the exception of curratively treated non-melanoma skin cancer or curatively treated cervical cancer. Additionally, patients curatively treated for malignancy who remain disease free at >2 years or follow up, are not excluded.

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