Study of Nivolumab in Combination With Ipilimumab Versus Nivolumab in Combination With Ipilimumab Placebo in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Study Overview
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Brief Summary
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A study in patients with metastatic or recurrent squamous cell cancer of the head and neck to evaluate the effectiveness of Nivolumab plus Ipilumumab vs. Nivolumab alone (CheckMate 714)

Official Title
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A Double-Blind, Randomized, Two Arm Phase 2 Study of Nivolumab in Combination With Ipilimumab Versus Nivolumab in Combination With Ipilimumab Placebo in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed squamous cell head and neck cancer Widespread (metastatic) disease, or returned after previous treatment (recurrent) Tumor sample must be available for analysis of PDL1 (Programmed death-ligand 1) and HPV [Human Papilloma Virus (oropharynx only)] Performance status ECOG 0-1 (Eastern Cooperative Oncology Group) Exclusion Criteria: Previous treatment for metastatic or recurrent disease Cancer arising from one of the following primary sites: paranasal sinus, nasopharynx, salivary gland, skin Any non-squamous subtype Active autoimmune disease Positive test for hepatitis B, C or HIV (Human Immunodeficiency Virus) virus Previous treatment with checkpoint inhibitor drugs Active CNS metastases or carcinomatous meningitis Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab and Ipilimumab<br>Specified dose on specified days | Biological: Nivolumab<br> <br> * Other names: Opdivo;Biological: Ipilimumab<br> <br> |
| Active Comparator: Nivolumab and Ipilimumab-placebo<br>Specified dose on specified days | Biological: Nivolumab<br> <br> * Other names: Opdivo;Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) as Determined by Blinded Independent Central Review (BIRC) - Platinum Refractory Subgroup | ORR is defined as best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Approximately up to 30 months (from FPFV to Data base lock) | 
| Duration of Response (DOR) as Determined by Blinded Independent Central Review (BIRC) - Platinum Refractory Subgroup | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. | Approximately up to 30 months (from FPFV to Data base lock) | 
| Time to Response (TTR) as Determined by Blinded Independent Central Review (BIRC) - Platinum Refractory Subgroup | Time to Response (TTR) for participants demonstrating a response (either CR or PR) was defined as the time from the date of randomization to the date of the first confirmed response. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Approximately up to 30 months (from FPFV to Data base lock) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) as Determined by Blinded Independent Central Review (BIRC) - Platinum Eligible Subgroup | ORR is defined as percentage of participants with a complete response (CR) or partial response (PR). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization to end of study. Approximately 63 Months | 
| Duration of Response (DOR) as Determined by Blinded Independent Central Review (BIRC) - Platinum Eligible Subgroup | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. | From randomization to disease progression or death. Approximately 63 Months | 
| Progression Free Survival (PFS) as Determined by Blinded Independent Central Review (BIRC) - Platinum Refractory Subgroup | The time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Progression Free Survival (PFS) as Determined by Blinded Independent Central Review (BIRC) - Platinum Eligible Subgroup | the time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Overall Survival (OS) | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. | From randomization to death. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Refractory Subgroup | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. | From randomization to death. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Eligible Subgroup | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. | From randomization to death. Approximately 63 Months | 
| ORR - Platinum Eligible Subgroup Based on HPV p-16 Status | ORR is defined as the best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization to end of study. Approximately 63 Months | 
| ORR - Platinum Eligible Subgroup Based on Tumor Mutation Burden (TMB) Biomarker | ORR is defined as the best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization to end of study. Approximately 63 Months | 
| ORR - Platinum Refractory Subgroup Based on HPV p-16 Status | ORR is defined as the best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization to end of study. Approximately 63 Months | 
| ORR - Platinum Refractory Subgroup Based on Tumor Mutation Burden (TMB) Biomarker | ORR is defined as the best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization to end of study. Approximately 63 Months | 
| Duration of Response (DOR) - Platinum Refractory Subgroup Based on HPV p-16 Status | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. | From randomization to disease progression or death. Approximately 63 Months | 
| Duration of Response (DOR) - Platinum Refractory Subgroup Based on Tumor Mutation Burden (TMB) Status | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb | From randomization to disease progression or death. Approximately 63 Months | 
| Progression Free Survival (PFS) - Platinum Refractory Subgroup Based on HPV p-16 Status | the time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Progression Free Survival (PFS) - Platinum Refractory Subgroup Based on Tumor Mutation Burden (TMB) Status | the time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Refractory Subgroup Based on HPV p-16 Status | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. | From randomization to death. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Refractory Subgroup Based on Tumor Mutation Burden (TMB) Status | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb | From randomization to death. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Eligible Subgroup Based on HPV p-16 Status | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. | From randomization to death. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Eligible Subgroup Based on Tumor Mutation Burden (TMB) Status | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb | From randomization to death. Approximately 63 Months | 
| Progression Free Survival (PFS) - Platinum Eligible Subgroup Based on Tumor Mutation Burden (TMB) Status | the time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Progression Free Survival (PFS) - Platinum Eligible Subgroup Based on HPV p-16 Status | the time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Duration of Response (DOR) - Platinum Eligible Subgroup Based on HPV p-16 Status | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Duration of Response (DOR) - Platinum Eligible Subgroup Based on Tumor Mutation Burden (TMB) Status | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor's genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Duration of Response (DOR) - Platinum Refractory Subgroup Based on PD-L1 Status | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| ORR - Platinum Refractory Subgroup Based on PD-L1 Expression | ORR is defined as the best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization to end of study. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Refractory Subgroup Based on PD-L1 Status | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay | From randomization to death. Approximately 63 Months | 
| Progression Free Survival (PFS) - Platinum Refractory Subgroup Based on PD-L1 Status | The time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| Duration of Response (DOR) - Platinum Eligible Subgroup Based on PD-L1 Status | The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months | 
| ORR - Platinum Eligible Subgroup Based on PD-L1 Expression | ORR is defined as the best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization to end of study. Approximately 63 Months | 
| Overall Survival (OS) - Platinum Eligible Subgroup Based on PD-L1 Status | Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay | From randomization to death. Approximately 63 Months | 
| Progression Free Survival (PFS) - Platinum Eligible Subgroup Based on PD-L1 Status | The time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to disease progression or death. Approximately 63 Months |