Study of Nivolumab in Patients With Classical Hodgkin's Lymphoma (Registrational)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B & C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants.

Official Title
-----------------
Non-Comparative, Multi-Cohort, Single Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in Classical Hodgkin Lymphoma (cHL) Subjects

Conditions
-----------------
Hodgkin Disease

Intervention / Treatment
-----------------
* Drug: Nivolumab
* Drug: Doxorubicin
* Drug: Vinblastine
* Drug: Dacarbazine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Must have received prior high-dose conditioning chemotherapy followed by autologous stem cell transplant (ASCT) as a part of salvage therapy for cHL (cohort A, B & C - enrollment closed) Participants may be Brentuximab vedotin- naïve, or may have had prior Brentuximab vedotin treatment (cohort A, B & C - enrollment closed) Newly diagnosed and previously untreated classical Hodgkin Lymphoma (cohort D) Exclusion Criteria: Known central nervous system lymphoma Participants with nodular lymphocyte-predominant Hodgkin Lymphoma Prior allogeneic stem cell transplantation (SCT) Chest radiation ≤ 24 weeks prior to first dose Carmustine ≥ 600 mg/m² received as part of the pre-transplant conditioning regimen

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab (Cohort A, B, C and D)<br>Cohort (A, B, C): Nivolumab: Specified dose on specified days Cohort (D): Nivolumab: Specified dose on specified days + Doxorubicin: Specified dose on specified days + Vinblastine: Specified dose on specified days + Dacarbazine: Specified dose on specified days | Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;Drug: Doxorubicin<br>* Specified dose on specified days<br>Drug: Vinblastine<br>* Specified dose on specified days<br>Drug: Dacarbazine<br>* Specified dose on specified days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Based on IRRC Assessments in Cohorts A, B, and C | ORR is the percent of participants achieving either a complete remission (CR) or partial remission (PR) according to the 2007 IWG criteria. Analyses of efficacy endpoints were performed separately for each cohort, according to IWG 2007. For cohort A and B, if the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. For cohort C, no evidence of FDG-avid disease in bone marrow was required in all participants in lieu of bone marrow aspirate/ biopsy. CR is the percent of participants with a best overall response (BOR) of CR (disappearance of all evidence of disease) according to the 2007 IWG criteria, based on IRRC assessment. PR is the percent of participants with a best overall response (BOR) of PR (regression of measurable disease and no new sites) according to the 2007 IWG criteria, based on IRRC assessment. Confidence interval based on Clopper-Pearson method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, whichever occurred first (up to approximately 28 months) | 
| Number of Participants Who Experienced at Least One Treatment Related Grade 3-5 AE in Cohort D | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. | From first dose of the considered therapy phase to 30 days after last dose of study therapy phase (or up to first dose of combination if any when considering the monotherapy period) (an average of 8 months and a maximum of 11 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Objective Response Based on IRRC Assessments in Cohorts A, B, and C | DOR is the time from first response (complete remission (CR) or partial remission (PR)) to the date of initial objectively documented progression as determined using the 2007 IWG criteria or death due to any cause, whichever occurred first. For participants who neither progressed nor died, the DOR was censored on the date of their last tumor assessment. Participants who started subsequent therapy without a prior reported progression were censored at the last tumor assessments prior to initiation of the subsequent anticancer therapy. CR is the percent of participants with a best overall response (BOR) of CR (disappearance of all evidence of disease) according to the 2007 IWG criteria, based on IRRC assessment. PR is the percent of participants with a best overall response (BOR) of PR (regression of measurable disease and no new sites) according to the 2007 IWG criteria, based on IRRC assessment. Computed using Kaplan-Meier method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months). | 
| Complete Remission (CR) Rate Based on IRRC Assessments in Cohorts A, B, and C | The CR rate was defined as the percent of participants with a BOR of CR (disappearance of all evidence of disease) according to the 2007 IWG criteria, based on IRRC assessment. Confidence interval based on Clopper-Pearson method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months) | 
| Duration of Complete Remission (CR) Based on IRRC Assessments for Cohorts A, B, and C | The duration of CR was only evaluated in participants with BOR of CR and was defined as the time from first documentation of CR (the date of first negative FDG-PET scan or the date of first documentation of no disease involvement in the bone marrow (if required), whichever occurred later) to the date of initial objectively documented progression (Any new lesion or increase by >=50% of previously involved sites from nadir) as determined using the 2007 IWG criteria or death due to any cause, whichever occurred first. Censoring was applied as per DOR definition. Computed using Kaplan-Meier method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months) | 
| Partial Remission (PR) Rate Based on IRRC Assessments in Cohorts A, B, and C | The PR rate was defined as the percent of participants with a BOR of PR (regression of measurable disease and no new sites) according to the 2007 IWG criteria, based on IRRC assessment. Confidence interval based on Clopper-Pearson method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months) | 
| Duration of PR Based on IRRC Assessments in Cohorts A, B, and C | The duration of PR was only evaluated in participants with BOR of PR and was defined as the time from first documentation of PR (regression of measurable disease and no new sites) to the date of initial objectively documented progression (any new lesion or increase by >=50% of previously involved sites from nadir) as determined using the 2007 IWG criteria or death due to any cause, whichever occurred first. Censoring was applied as per DOR definition. Computed using Kaplan-Meier method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months) | 
| Objective Response Rates (ORR) Based on Investigator Assessments for Cohorts A, B, and C | ORR is the percent of participants achieving either a complete remission (CR) or partial remission (PR) according to the 2007 IWG criteria. Analyses of efficacy endpoints were performed separately for each cohort, according to IWG 2007. For cohort A and B, if the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. For cohort C, no evidence of FDG-avid disease in bone marrow was required in all participants in lieu of bone marrow aspirate/ biopsy. CR is the percent of participants with a best overall response (BOR) of CR (disappearance of all evidence of disease) according to the 2007 IWG criteria, based on IRRC assessment. PR is the percent of participants with a best overall response (BOR) of PR (regression of measurable disease and no new sites) according to the 2007 IWG criteria, based on IRRC assessment. Confidence interval based on Clopper-Pearson method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months) | 
| Duration of Objective Response (DOR) Based on Investigator Assessments in Cohorts A, B, and C | DOR is the time from first response (complete remission (CR) or partial remission (PR)) to the date of initial objectively documented progression as determined using the 2007 IWG criteria or death due to any cause, whichever occurred first. For participants who neither progressed nor died, the DOR was censored on the date of their last tumor assessment. Participants who started subsequent therapy without a prior reported progression were censored at the last tumor assessments prior to initiation of the subsequent anticancer therapy. CR is the percent of participants with a best overall response (BOR) of CR (disappearance of all evidence of disease) according to the 2007 IWG criteria, based on IRRC assessment. PR is the percent of participants with a best overall response (BOR) of PR (regression of measurable disease and no new sites) according to the 2007 IWG criteria, based on IRRC assessment. Computed using Kaplan-Meier method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months) | 
| Treatment Discontinuation Rate in Cohort D | Treatment discontinuation rate (TDR) is the number of treated participants who received <4 doses of monotherapy or <12 doses of their assigned combination regimen. A participant is considered as having received an AVD/NAVD dose as soon as they received at least one drug of AVD/NAVD for the considered dose. Participants must have received at least one dose of Nivolumab during the combination therapy phase to be included in participants treated with NAVD. If a participant subsequently met Criteria to Resume Nivolumab Dosing, the combination of nivolumab and AVD could be used. Participants who underwent treatment beyond progression during the Monotherapy phase could use the combination of nivolumab and AVD if all 4 doses of nivolumab monotherapy are completed. Discontinuation can be due to any reason including, but not limited to, drug-related toxicity, diseases progression, or death. | From first dose up until the date of treatment discontinuation (up to approximately 100 months). | 
| Number of Participants Who Died in Cohort D | Number of participants who died in Cohort D within 100 days after last dose of study therapy. | From first dose of the considered therapy phase to 100 days after last dose of study therapy phase (or up to first dose of combination if any when considering the monotherapy period) (an average of 10 months up to a maximum of 13 months) | 
| Number of Participants With Adverse Events (AEs) in Cohort D | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | From first dose of the considered therapy phase to 30 days after last dose of study therapy phase (or up to first dose of combination if any when considering the monotherapy period) (an average of 8 months and a maximum of 11 months) | 
| Number of Participants With Serious Adverse Events (SAEs) in Cohort D | A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | From first dose of the considered therapy phase to 30 days after last dose of study therapy phase (or up to first dose of combination if any when considering the monotherapy period) (an average of 8 months and a maximum of 11 months) | 
| Number of Participants With AEs Leading to Discontinuation in Cohort D | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | From first dose of the considered therapy phase to 30 days after last dose of study therapy phase (or up to first dose of combination if any when considering the monotherapy period) (an average of 8 months and a maximum of 11 months) | 
| Number of Participants With AEs Leading to Dose Delay in Cohort D | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | From first dose of the considered therapy phase to 30 days after last dose of study therapy phase (or up to first dose of combination if any when considering the monotherapy period) (an average of 8 months and a maximum of 11 months) | 
| Number of Participants With Select AEs in Cohort D | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Select AEs have been categorized into seven areas: pulmonary toxicity, gastrointestinal toxicity, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity and renal toxicity. Select AEs, in particular pneumonitis, are considered clinically meaningful as they require greater vigilance and for early recognition and prompt intervention. | From first dose of the considered therapy phase to 30 days after last dose of study therapy phase (or up to first dose of combination if any when considering the monotherapy period) (an average of 8 months and a maximum of 11 months) | 
| Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests in Cohort D Monotherapy Phase | The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal | From first dose of monotherapy to 30 days after last dose of monotherapy phase (up to approximately 3 months) | 
| Number of Participants Laboratory Abnormalities in Specific Thyroid Tests in Cohort D Combination Therapy Phase | The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal | From first dose of the combination therapy to 30 days after last dose of combination therapy (an average of 8 months and a maximum of 11 months) | 
| Number of Participants With Laboratory Abnormalities in Specific Liver Tests in Cohort D Monotherapy Phase | The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase, AST = Aspartate Aminotransferase, ULN = Upper Limit of Normal. | From first dose of monotherapy to 30 days after last dose of monotherapy phase (up to approximately 3 months) | 
| Number of Participants With Laboratory Abnormalities in Specific Liver Tests in Cohort D Combination Therapy Phase | The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase, AST = Aspartate Aminotransferase, ULN = Upper Limit of Normal. | From first dose of the combination therapy to 30 days after last dose of combination therapy (an average of 8 months and a maximum of 11 months) | 
| Complete Response (CR) Rate at Planned End of Therapy Based on IRRC Assessments in Cohort D | CR rate is the percent of participants who show CR (disappearance of all evidence of disease) according to the 2007 IWG criteria at the planned end of study therapy radiographic tumor assessment. Confidence interval based on the Klopper and Pearson method. | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, or death whichever occurred first (up to approximately 100 months) |