An Investigational Immuno-therapy Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas

Study Overview
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Brief Summary
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The purpose of this study is to determine whether Nivolumab, in combination with brentuximab vedotin, is safe and effective in patients with certain subtypes of non-Hodgkin's lymphomas with CD30 expression that have not responded to treatment or have come back. The subtypes we are studying are Diffuse Large B-Cell Lymphoma (DLBCL), Peripheral T-Cell Lymphoma (PTCL), Cutaneous T-Cell Lymphoma (CTCL), Primary Mediastinal Large B-Cell Lymphoma (PMBL) and Mediastinal Gray Zone Lymphoma (MGZL).

Official Title
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A Phase I/ II Study to Evaluate the Safety and Preliminary Efficacy of Nivolumab in Combination With Brentuximab Vedotin in Subjects With Relapsed Refractory Non Hodgkin Lymphomas With CD30 Expression (CheckMate 436: CHECKpoint Pathway and Nivolumab Clinical Trial Evaluation 436)

Conditions
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Non-Hodgkin's Disease

Intervention / Treatment
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* Biological: Nivolumab
* Drug: Brentuximab Vedotin


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Relapsed/refractory diffuse large B cell lymphoma (DLBCL), relapsed/refractory peripheral T cell lymphoma (PTCL) (all subtypes excluding anaplastic large cell lymphoma), relapsed/refractory Cutaneous T cell lymphoma (CTCL) mycosis fungoides/sezary syndrome (MF/SS), relapsed/refractory primary mediastinal B lymphoma (PMBL), and relapsed/refractory mediastinal gray zone lymphoma (MGZL) Expression of CD30 Subjects must be 18 years or older (≥ 15 years for PMBL) Exclusion Criteria: Known central nervous system (CNS) lymphomas; Active cerebral/meningeal disease related to the underlying malignancy Active, known, or suspected autoimmune disease

Ages Eligible for Study
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Minimum Age: 15 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab+Brentuximab Vedotin<br>Nivolumab+Brentuximab Vedotin dose as specified | Biological: Nivolumab<br> <br> Drug: Brentuximab Vedotin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Analysis - Number of Participants With Dose Limiting Toxicities (DLT) in the DLT Evaluation Phase | DLTs are defined as any study drug-related toxicity (brentuximab vedotin or nivolumab) that requires either a dose reduction or delay of more than 7 days of either study drug in Cycle 2 or delays the Cycle 3 Day 1 administration of combined treatment by more than 7 days. | From first dose of treatment to 6 weeks after first dose | 
| Safety Analysis - Number of Participant Deaths | Number of participant Deaths | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Safety Analysis - Number of Participants With Adverse Advents | 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. | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Safety Analysis - Number of Participants With Serious Adverse Events | 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. results in persistent or significant disability/incapacity is a congenital anomaly/birth defect is an important medical event | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Safety Analysis - Number of Participants With Adverse Events Leading to Discontinuation | Number of participants with adverse events leading to discontinuation | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Safety Analysis - Number of Participants With Adverse Events Leading to Dose Delay or Reduction | Number of participants with adverse events leading to dose delay or reduction | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Safety Analysis - Number of Participants With Drug Related Adverse Events | Number of participants with Drug Related Adverse Events | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Safety Analysis - Percentage of Participants With Thyroid Test Abnormalities | Percentage of participants with specific thyroid test abnormalities | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Safety Analysis - Percentage of Participants With Liver Test Abnormalities | Percentage of participants with specific Liver test abnormalities | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 
| Objective Response Rate (ORR) | The percentage of participants with a best overall response (BOR) of CR or PR. DLBCL, PTCL, PMBL & MGZL complete and partial response are outlined in the Lugano Classification 2014 and Lymphoma Response to Immunomodulatory therapy Criteria. CTCL complete and partial response are defined in The consensus Global Response Score assessment. | CTCL: 20 Months, PTCL: 26.5 Months, DLBCL: 26 Months, MGZL: 30 Months and PMBL 25.5 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR will be calculated from the date of initial documentation of a response (CR, or PR) to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death due to any cause, whichever occurs first. DLBCL, PTCL, PMBL & MGZL complete and partial response are outlined in the Lugano Classification 2014 and Lymphoma Response to Immunomodulatory therapy Criteria. CTCL complete and partial response are defined in The consensus Global Response Score assessment. | From the first patient first visit to 8 months after the last patient first visit (up to 48 months) | 
| Complete Response Rate (CRR) | The CRR is defined as the percentage of participants with a BOR (Best overall response) of CR divided by the number of treated participants. DLBCL, PTCL, PMBL & MGZL (CR) 1.Complete disappearance of all detectable clinical evidence of disease. 2.Bone marrow: No evidence of FDG- avid disease in marrow. CTCL (CR) 100% clearance of skin lesions. all lymph nodes ≤1.5 cm, N3 classification and ≤ 1.5 cm in their long axis and > 1 cm in their short axis at baseline, must be ≤ 1 cm in their short axis or biopsy negative for lymphoma. organs should not be enlarged on examination or imaging absence of blood involvement | From first dose to the date of initial objectively documented progression or the date of subsequent therapy, whichever occurs first (up to 48 months) | 
| Duration of Complete Response | The duration of CR will only be evaluated in participants with BOR of CR and is defined as the time from first documentation of CR to the date of relapse or death due to any cause, whichever occurs first. DLBCL, PTCL, PMBL & MGZL (CR) 1.Complete disappearance of all detectable clinical evidence of disease. 2.Bone marrow: No evidence of FDG- avid disease in marrow. CTCL (CR) 100% clearance of skin lesions. all lymph nodes ≤1.5 cm, N3 classification and ≤ 1.5 cm in their long axis and > 1 cm in their short axis at baseline, must be ≤ 1 cm in their short axis or biopsy negative for lymphoma. organs should not be enlarged on examination or imaging absence of blood involvement | From first dose to the date of relapse or death due to any cause, whichever occurs first. (about 48 months) | 
| Progression Free Survival (PFS) | PFS is defined as the time from the date of first dose of study drug until the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death due to any cause, whichever comes first. Participants who are progression-free and alive or have unknown status will be censored at the last tumor assessment. Participants who did not have any onstudy tumor assessments and did not die will be censored on the date of first treatment. For participants who received subsequent therapy prior to documented progression, it will be censored on the last tumor assessment date prior to or on subsequent therapy. | From first dose of study drug until the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death due to any cause, whichever comes first. (about 48 months) | 
| Overall Survival (OS) | OS is defined as the time from the date of first dose of study drug until the date of death (any reason). If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant was last known to be alive. | From the first patient first visit to 8 months after the last patient first visit (about 48 months) |