An Investigational Immuno-therapy Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas (CheckMate 436)

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)

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).

Study Overview

• Status: Completed
• Conditions: Non-Hodgkin's Disease
• Intervention / Treatment: Biological: Nivolumab; Drug: Brentuximab Vedotin

• Study Type: Interventional
• Enrollment (Actual): 145
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer Agency - Vancouver Centre
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution - 0011
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• France
  • Paris, France, 75010
    • Hopital Saint Louis
  • Pierre Benite Cedex, France, 69495
    • Local Institution - 0020
• Italy
  • Bergamo, Italy
    • Local Institution - 0018
  • Bologna, Italy, 40126
    • Local Institution - 0024
  • Rozzano (milano), Italy, 20089
    • Istituto Clinico Humanitas
• Spain
  • Hospitalet de Llobregat - Barcelona, Spain, 08908
    • Local Institution - 0027
• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LJ
      • Churchill Hospital
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • Local Institution - 0017
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • Local Institution - 0012
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute.
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10021
      • Local Institution - 0003
    • New York, New York, United States, 10029
      • Local Institution - 0010
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Bon Secours-St Francis Hosp
  • Washington
    • Seattle, Washington, United States, 98109-1023
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab+Brentuximab Vedotin; Nivolumab+Brentuximab Vedotin dose as specified	Biological: Nivolumab; Drug: Brentuximab Vedotin

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Seagen Inc.

Publications and helpful links

General Publications

• Zinzani PL, Santoro A, Gritti G, Brice P, Barr PM, Kuruvilla J, Cunningham D, Kline J, Johnson NA, Mehta-Shah N, Manley T, Francis S, Sharma M, Moskowitz AJ. Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study. J Clin Oncol. 2019 Nov 20;37(33):3081-3089. doi: 10.1200/JCO.19.01492. Epub 2019 Aug 9.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2016
• Primary Completion (Actual): January 16, 2020
• Study Completion (Actual): February 7, 2022

Study Registration Dates

• First Submitted: October 13, 2015
• First Submitted That Met QC Criteria: October 19, 2015
• First Posted (Estimate): October 21, 2015

Study Record Updates

• Last Update Posted (Estimate): March 7, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Brentuximab Vedotin
• Other Study ID Numbers: CA209-436; 2015-003286-28 (EudraCT Number)