Clinical Trial: NCT03811015 - My Cancer Genome

NCT03811015

Description:

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 (throat 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.

Related Conditions:

Oropharyngeal Carcinoma

Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

URL:

https://clinicaltrials.gov/show/NCT03811015

Trial Eligibility

Document

Title

Brief Title: Testing Immunotherapy Versus Observation in Patients With HPV Throat Cancer
Official Title: A Phase II/III Randomized Study of Maintenance Nivolumab Versus Observation in Patients With Locally Advanced, Intermediate Risk HPV Positive OPSCC

Clinical Trial IDs

ORG STUDY ID: NCI-2019-00179
SECONDARY ID: NCI-2019-00179
SECONDARY ID: EA3161
SECONDARY ID: EA3161
SECONDARY ID: U10CA180820
NCT ID: NCT03811015

Conditions

Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8

Interventions

Drug	Synonyms	Arms
Cisplatin	Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin	Arm A (cisplatin, IMRT, nivolumab)
Nivolumab	BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo	Arm A (cisplatin, IMRT, nivolumab)

Purpose

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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). (Phase II) II. 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). (Phase III)

      SECONDARY OBJECTIVES:

      I. To further assess the efficacy of nivolumab compared with observation in terms of:

      Ia. The relationship of baseline PD-L1 expression to clinical outcome. Ib. To evaluate the
      association of 12 week post therapy fludeoxyglucose F-18 (FDG) positron emission
      tomography(PET)/computed tomography (CT) with PFS and OS.

      Ic. To establish the prognostic value of standardized uptake value (SUV)max of primary tumor
      or neck nodal metastasis of baseline FDG PET/CT for OS (and/or PFS).

      Id. To correlate SUVmax of primary tumor or nodal metastasis of baseline FDG PET/CT with
      PD-L1 expression (positive vs. negative).

      Ie. To compare the PET based therapy response assessment (Hopkins criteria) to the Response
      Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessment at 12 week post chemoradiation
      therapy, for patients who have a PET/CT scan at 12 weeks.

      OUTLINE: Patients are randomized to Arm A or Arm B. Patients in Arm B may cross-over to Arm C
      with clearly documented disease progression.

      ARM A: Patients receive cisplatin intravenously (IV) over 60 minutes weekly and intensity
      modulated radiation therapy (IMRT) 5 days a week for 7 weeks for a total of 35 fractions.
      Within 4 weeks after completion of concurrent therapy, patients receive nivolumab IV once
      weekly over 30 minutes every 4 weeks for 12 months in the absence of disease progression or
      unacceptable toxicity.

      ARM B: Patients receive cisplatin IV over 60 minutes weekly and IMRT 5 days a week for 7
      weeks for a total of 35 fractions, and then go on observation. Patients will be offered the
      option to cross-over to Arm C if they have clearly documented progression within 12 months
      from the end of cisplatin/radiation therapy.

      ARM C: Patients receive nivolumab IV over 30 minutes every 4 weeks for 12 months in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3-6 months for 3 years
      and then annually for a total of 10 years.

Trial Arms

Name	Type	Description	Interventions
Arm A (cisplatin, IMRT, nivolumab)	Experimental	Patients receive cisplatin IV over 60 minutes weekly and IMRT 5 days a week for 7 weeks for a total of 35 fractions. Within 4 weeks after completion of concurrent therapy, patients receive nivolumab IV once weekly over 30 minutes every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity.	Cisplatin Nivolumab
Arm B (cisplatin, IMRT, observation)	Active Comparator	Patients receive cisplatin IV over 60 minutes weekly and IMRT 5 days a week for 7 weeks for a total of 35 fractions, and then go on observation. Patients will be offered the option to cross-over to Arm C if they have clearly documented progression within 12 months from the end of cisplatin/radiation therapy.	Cisplatin
Arm C (nivolumab)	Experimental	Patients receive nivolumab IV over 30 minutes every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity.	Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  STEP 1: Patients must have oropharynx cancer (American Joint Committee on Cancer
             [AJCC] 8) that is p16-positive by immunohistochemistry with smoking status: >= 10
             pack-years, stage T1-2N2-N3 or T3-4N0-3 (less than 10 pack-years is considered a
             non-smoker) OR < 10 pack-years, stage T4N0-N3 or T1-3N2-3.

          -  STEP 1: Patients must not have known hypersensitivity to nivolumab or compounds of
             similar chemical or biologic composition.

          -  STEP 1: Patients with a history of allergic reactions attributed to platinum-based
             chemotherapy agents are excluded.

          -  STEP 1: Patients must not have had prior systemic therapy, radiation treatment or
             surgery for p16 positive oropharyngeal squamous cell carcinoma (OPSCC).

          -  STEP 1: Patients must not have received previous irradiation for head and neck tumor,
             skull base, or brain tumors.

          -  STEP 1: Patients must not receive investigational agents within 4 weeks of enrollment
             or at any time while on study.

          -  STEP 1: Patients with evidence of distant metastases or leptomeningeal disease (LMD)
             are excluded.

          -  STEP 1: Patients with uncontrolled inter-current illnesses which in the opinion of the
             investigator will interfere with the ability to undergo therapy including chemotherapy
             are excluded.

          -  STEP 1: Patients with a history of prior or second malignancy are excluded, with the
             exception of curatively treated non-melanoma skin cancer, or curatively treated
             cervical cancer; additionally, patients curatively treated for malignancy who remain
             disease-free at > 2 years of follow up, are not excluded.

          -  STEP 1: Absolute neutrophil count (ANC) >= 1500/mm^3 (must be obtained =< 2 weeks
             prior to randomization).

          -  STEP 1: Hemoglobin (Hgb) >= 8.0 g/dL (must be obtained =< 2 weeks prior to
             randomization).

          -  STEP 1: Platelet count >= 100,000/mm^3 (must be obtained =< 2 weeks prior to
             randomization).

          -  STEP 1: Creatinine clearance of >= 60 ml/min (must be obtained =< 2 weeks prior to
             randomization). Creatinine clearance may be measured or calculated. If calculating,
             creatinine clearance, use the Cockcroft-Gault formula.

          -  STEP 1: Total bilirubin within 1.5 times the normal limits (must be obtained =< 2
             weeks prior to randomization).

          -  STEP 1: 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 =< 2 weeks prior to
             randomization).

          -  STEP 1: Alkaline phosphatase within 1.5 times the normal limits (must be obtained =< 2
             weeks prior to randomization).

          -  STEP 1: Women 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 patients to have an uninterrupted
             therapy.

        All women of childbearing potential must have a blood test or urine study within 2 weeks
        prior to randomization to rule out pregnancy.

        A woman of childbearing potential is any female, regardless of sexual orientation or
        whether they have undergone tubal ligation, who meets the following criteria: 1) has
        achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
        oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer
        therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e.,
        has had menses at any time in the preceding 24 consecutive months).

          -  STEP 1: 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.

          -  STEP 1: Patients must have measurable disease as defined.

          -  STEP 1: Patients 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.

          -  STEP 2: Patients must have progression per RECIST criteria AND tissue-proven
             progression on Arm B treatment within 12 months after completion of radiation therapy.

          -  STEP 2: ECOG performance status of 0 or 1.

          -  STEP 2: Patients must not have known hypersensitivity to nivolumab or compounds of
             similar chemical or biologic composition.

          -  STEP 2: Patients must not have received non-protocol anti-cancer therapy after
             completion of radiation and chemotherapy.

          -  STEP 2: ANC >= 1500/mm^3 (must be obtained =< 2 weeks prior to registration).

          -  STEP 2: Hgb >= 8.0 g/dL (must be obtained =< 2 weeks prior to registration).

          -  STEP 2: Platelet count >= 100,000/mm^3 (must be obtained =< 2 weeks prior to
             registration).

          -  STEP 2: Creatinine clearance of >= 60 ml/min (must be obtained =< 2 weeks prior to
             registration). Creatinine clearance may be measured or calculated. If calculating,
             creatinine clearance, use the Cockcroft-Gault formula.

          -  STEP 2: Total bilirubin within 1.5 times the normal limits (must be obtained =< 2
             weeks prior to registration).

          -  STEP 2: SGOT (AST) or SGPT (ALT) within 2.0 times the normal limits (must be obtained
             =< 2 weeks prior to registration).

          -  STEP 2: Alkaline phosphatase within 1.5 times the normal limits (must be obtained =< 2
             weeks prior to registration).

          -  STEP 2: Women 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 patients to have an uninterrupted
             therapy.

        All women of childbearing potential must have a blood test or urine study within 2 weeks
        prior to registration to rule out pregnancy.

        A women of childbearing potential is any female, regardless of sexual orientation or
        whether they have undergone tubal ligation, who meets the following criteria: 1) has
        achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
        oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer
        therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e.,
        has had menses at any time in the preceding 24 consecutive months).

          -  STEP 2: 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.

          -  STEP 2: Patients must have measurable disease.

          -  STEP 2: Patients 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.

Maximum Eligible Age:	N/A
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Progression-free survival (PFS) (Phase II)
Time Frame:	From randomization to date of progression, second primary tumor from the head and neck region, or death, assessed up to 10 years
Safety Issue:
Description:	Progression will be defined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Log rank test will be used to compare PFS and OS. Both phase II and phase III analyses will be intent-to-treat analysis, and analysis will be stratified on stratification factors collected at the time of randomization. As patients on the observation arm are allowed to cross-over to the nivolumab arm upon progression, an overall survival analysis using inverse probability censoring weights (IPCW, Robins et. al, 2000) will also be considered. Kaplan-Meier method and Cox regression will be used for the survival outcome analyses.

Secondary Outcome Measures

Measure:	Prognostic effect of baseline PD-L1 expression (positive versus [vs.] negative) on OS and PFS
Time Frame:	Baseline up to 10 years
Safety Issue:
Description:	Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.

Measure:	Prognostic effect of baseline saliva and/or plasma human papillomavirus (HPV) status (positive vs. negative) on OS and PFS
Time Frame:	Baseline up to 10 years
Safety Issue:
Description:	Saliva and plasma HPV status at 12 weeks and 9 months following completion of concurrent therapy will also be analyzed regarding effect on outcome. Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.

Measure:	Prognostic value of maximum standardized uptake value (SUVmax) of primary tumor or neck nodal metastasis of baseline FDG PET/CT for OS
Time Frame:	Baseline up to 10 years
Safety Issue:
Description:	Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.

Measure:	Prognostic value of SUVmax of primary tumor or neck nodal metastasis of baseline FDG PET/CT for PFS
Time Frame:	Baseline up to 10 years
Safety Issue:
Description:	Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.

Measure:	SUVmax of primary tumor or nodal metastasis of baseline FDG PET/CT with PD-L1 expression (positive vs. negative)
Time Frame:	Baseline up to 10 years
Safety Issue:
Description:	Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.

Measure:	Post therapy (cisplatin + RT) FDG PET/CT with saliva or plasma levels of HPV deoxyribonucleic acid (DNA)
Time Frame:	Up to 9 months post-therapy
Safety Issue:
Description:	Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.

Measure:	PET based therapy response assessment compared to RECIST 1.1 assessment for patients who have a PET/CT scan at 12 weeks
Time Frame:	At 12 weeks post chemoradiation therapy
Safety Issue:
Description:	Kappa statistics will be applied to evaluate the agreement between PET based therapy response assessment (Hopkins criteria) and RECIST 1.1 assessment at 12 weeks post chemoradiation therapy.

Details

Phase:	Phase 2/Phase 3
Primary Purpose:	Interventional
Overall Status:	Recruiting
Lead Sponsor:	National Cancer Institute (NCI)

Last Updated

August 27, 2021

Clinical Trials /

Testing Immunotherapy Versus Observation in Patients With HPV Throat Cancer