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Trial record 1 of 1 for:    EA3161
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Testing Immunotherapy Versus Observation in Patients With HPV Throat Cancer

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ClinicalTrials.gov Identifier: NCT03811015
Recruitment Status : Recruiting
First Posted : January 22, 2019
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE January 18, 2019
First Posted Date  ICMJE January 22, 2019
Last Update Posted Date January 22, 2021
Actual Study Start Date  ICMJE June 20, 2019
Estimated Primary Completion Date January 1, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 16, 2019)
  • 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 ]
    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.
  • Overall survival (OS) (Phase III) [ Time Frame: From randomization to death, assessed up to 10 years ]
    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.
  • Negative (standardized qualitative) 12 week post therapy (cisplatin + radiation therapy [RT]) FDG positron emission tomography/computed tomography (PET/CT) associated with OS for patients who have a PET/CT [ Time Frame: At 12 weeks post therapy ]
    Logrank tests and input hazard rates will be used.
  • Negative (standardized qualitative) 12 week post therapy (cisplatin + RT) FDG PET/CT associated with PFS for patients who have a PET/CT [ Time Frame: At 12 weeks post therapy ]
    Logrank tests and input hazard rates will be used.
Original Primary Outcome Measures  ICMJE
 (submitted: January 18, 2019)
  • 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 24 months ]
    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.
  • Overall survival (OS) (Phase III) [ Time Frame: From randomization to death, assessed up to 24 months ]
    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.
  • Negative (standardized qualitative) 12 week post therapy (cisplatin + radiation therapy [RT]) FDG positron emission tomography/computed tomography (PET/CT) associated with OS for patients who have a PET/CT [ Time Frame: At 12 weeks ]
    Logrank tests and input hazard rates will be used.
  • Negative (standardized qualitative) 12 week post therapy (cisplatin + RT) FDG PET/CT associated with PFS for patients who have a PET/CT [ Time Frame: At 12 weeks ]
    Logrank tests and input hazard rates will be used.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2019)
  • Prognostic effect of baseline PD-L1 expression (positive versus [vs.] negative) on OS and PFS [ Time Frame: Baseline up to 10 years ]
    Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
  • 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 ]
    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.
  • 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 ]
    Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
  • 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 ]
    Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
  • 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 ]
    Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
  • 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 ]
    Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Testing Immunotherapy Versus Observation in Patients With HPV Throat Cancer
Official Title  ICMJE A Phase II/III Randomized Study of Maintenance Nivolumab Versus Observation in Patients With Locally Advanced, Intermediate Risk HPV Positive OPSCC
Brief 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 (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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Cisplatin
    Given IV
    Other Names:
    • 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
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
    • Radiation, Intensity-Modulated Radiotherapy
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Other: Patient Observation
    Undergo observation
    Other Names:
    • Active Surveillance
    • deferred therapy
    • expectant management
    • Observation
    • Watchful Waiting
Study Arms  ICMJE
  • Experimental: Arm A (cisplatin, IMRT, nivolumab)
    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.
    Interventions:
    • Drug: Cisplatin
    • Radiation: Intensity-Modulated Radiation Therapy
    • Biological: Nivolumab
  • Active Comparator: Arm B (cisplatin, IMRT, observation)

    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.

    Interventions:
    • Drug: Cisplatin
    • Radiation: Intensity-Modulated Radiation Therapy
    • Other: Patient Observation
  • Experimental: Arm C (nivolumab)
    Patients receive nivolumab IV over 30 minutes every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 18, 2019)
744
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2027
Estimated Primary Completion Date January 1, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03811015
Other Study ID Numbers  ICMJE NCI-2019-00179
NCI-2019-00179 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA3161 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA3161 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Nabil F Saba ECOG-ACRIN Cancer Research Group
PRS Account National Cancer Institute (NCI)
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP