Study of Nivolumab in Subjects With Relapsed or Refractory Follicular Lymphoma (FL) (CheckMate 140)

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02038946
• Collaborator: (none)
• Enrollment: 116
• Locations: 45
• Arm: 1
• Actual Duration (Months): 81.1
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the clinical benefit of Nivolumab, as measured by independent radiologic review committee (IRRC)-assessed objective response rate (ORR) in subjects with FL lymphoma who have failed therapy with both CD20 antibody and an alkylating agent.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: Nivolumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Open-Label Phase 2 Study of Nivolumab (BMS-936558) in Subjects With Relapsed or Refractory Follicular Lymphoma (FL)
• Actual Study Start Date: Mar 26, 2014
• Actual Primary Completion Date: May 17, 2017
• Actual Study Completion Date: Dec 28, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: Nivolumab Nivolumab 3 mg/kg injection by Intravenous for every 2 weeks until disease progression or discontinuation due to toxicity	Drug: Nivolumab; Other Names: BMS-936558

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) as Determined by IRRC [From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)]

   ORR is determined by an independent radiologic review committee (IRRC) according to the revised International Working Group Criteria for non-Hodgkin Lymphoma. ORR is defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) and expressed as a percentage of all treated participants. CR=Disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of spleen, liver, and bone marrow involvement. PR=Regression of measurable disease and no new sites; no increase in size of liver or spleen. >=50% decrease in SPD of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions)

Secondary Outcome Measures

1. Duration of Response (DOR) Based on IRRC Assessments [From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)]

   DOR is defined as the time from first remission (CR or PR) to the date of initial objectively documented progression as determined using the revised International Working Group Criteria for non-Hodgkin Lymphoma, or death due to any cause, whichever occurs first. CR definition includes the complete disappearance of all evidence of disease, the definition of PR includes at least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses, and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir, as described in the IWG response criteria

2. Complete Remission Rate (CRR) Based on IRRC Assessment [From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)]

   CRR is defined as the number of subjects with a BOR of CR according to the revised International Working Group Criteria for non-Hodgkin Lymphoma, divided by the number of treated participants and expressed as a percentage. CR=Disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of spleen, liver, and bone marrow involvement.

3. Partial Remission (PR) Rate Based on IRRC Assessment [From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)]

   PR rate is defined as the number of participants with a best overall response (BOR) of PR according to the 2007 International Working Group (IWG) criteria, based on IRRC assessment, divided by the number of treated participants and expressed as a percentage. PR=Regression of measurable disease and no new sites; no increase in size of liver or spleen. >=50% decrease in SPD of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions)

4. Progression Free Survival (PFS) Based on IRRC Assessment [From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)]

   PFS was summarized descriptively using the Kaplan-Meier (KM) product-limit method. Median values of PFS, along with the two-sided 95% CIs were calculated using a method based on log-log transformation.

5. Overall Response Rate (ORR) Based on Investigator Assessments [From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)]

   ORR is determined by investigator assessments according to the revised International Working Group Criteria for non-Hodgkin Lymphoma. ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) and is expressed as a percentage of all treated participants. CR=Disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of spleen, liver, and bone marrow involvement. PR=Regression of measurable disease and no new sites; no increase in size of liver or spleen. >=50% decrease in SPD of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Grade 1, 2, or 3a FL without pathologic evidence of transformation

• Male and female, ages 18 and above, with relapsed or refractory FL lymphoma after > or =2 prior treatment lines; each of the 2 prior treatment lines must include at least CD20 antibody and/or an alkylating agent

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1

Exclusion Criteria:

• Known central nervous system lymphoma

• History of interstitial lung disease

• Subjects with active, known or suspected autoimmune disease

• Prior allogeneic stem cell transplant

• Prior autologous stem cell transplant ≤12 weeks prior to first dose of study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054
2	Division Of Hematology & Oncology Ctr. For Health Sciences	Los Angeles	California	United States	90095
3	Winship Cancer Institute.	Atlanta	Georgia	United States	30322
4	Beth Israel Deaconess Medical Center (BIDMC)	Boston	Massachusetts	United States	02215
5	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02215
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Weill Cornell Medical College	New York	New York	United States	10021
9	Duke University Medical Center	Durham	North Carolina	United States	27710
10	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
11	MD Anderson Cancer Center	Houston	Texas	United States	77030
12	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
13	Local Institution	Woodville	South Australia	Australia	5011
14	Local Institution	Parkville	Victoria	Australia	3050
15	Local Institution	B-leuven		Belgium	3000
16	Local Institution	Bruxelles		Belgium	1200
17	Local Institution	Gent		Belgium	9000
18	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
19	CISSS du Bas-Saint-Laurent Hopital Regional de Rimouski	Rimouski	Quebec	Canada	G5L 5T1
20	Local Institution	Creteil		France	94010
21	Local Institution	Montpellier Cedex 05		France	34295
22	Local Institution	Pierre Benite Cedex		France	69495
23	Local Institution	Rennes		France	35033
24	Universitaetsklinikum Essen	Essen		Germany	45147
25	Universitaetsklinikum d. Saarlandes	Homburg		Germany	66424
26	Universitaetsklinikum Des Saarlandes	Homburg		Germany	66424
27	Local Institution	Regensburg		Germany	93053
28	Universitaetsklinikum Ulm	Ulm		Germany	89081
29	Local Institution	Bergamo		Italy	24127
30	Local Institution	Bologna		Italy	40138
31	Local Institution	Milano		Italy	20133
32	Local Institution	Napoli		Italy	80131
33	Local Institution	Roma		Italy	00161
34	Local Institution	Oslo		Norway	0424
35	Local Institution	Singapore		Singapore	169865
36	Local Institution	Singapore		Singapore	308433
37	Hospital Duran I Reynals	Hospitalet Llobregat- Barcelona		Spain	9908
38	Local Institution	Madrid		Spain	28009
39	Hospital Universitario La Paz	Madrid		Spain	28046
40	Local Institution	Salamanca		Spain	37007
41	Local Institution	Gothenberg		Sweden	413 45
42	Local Institution	Gothenburg		Sweden	413 45
43	Local Institution	Southampton	Hampshire	United Kingdom	SO16 6YD
44	Local Institution	Withington	Manchester	United Kingdom	M20 4BX
45	Local Institution	Sutton	Surrey	United Kingdom	SM2 5PT

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

• Study Protocol - Jul 21, 2016
• Statistical Analysis Plan - Jun 27, 2017

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02038946
• Other Study ID Numbers: CA209-140; 2013-003645-42
• First Posted: Jan 17, 2014
• Last Update Posted: Jan 4, 2022
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Nivolumab

Study Results

Participant Flow

Pre-assignment Detail	116 participants were enrolled; 92 received study treatment. Participants were enrolled but not treated because they no longer met study criteria (n=20), withdrew consent (n=1), or for other reasons (n=3).

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Period Title: Overall Study
STARTED	92
COMPLETED	80
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Overall Participants	92
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.2 (10.50)
Sex: Female, Male (Count of Participants)
Female	44 47.8%
Male	48 52.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 5.4%
Not Hispanic or Latino	49 53.3%
Unknown or Not Reported	38 41.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 3.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 1.1%
White	87 94.6%
More than one race	0 0%
Unknown or Not Reported	1 1.1%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) as Determined by IRRC
Description	ORR is determined by an independent radiologic review committee (IRRC) according to the revised International Working Group Criteria for non-Hodgkin Lymphoma. ORR is defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) and expressed as a percentage of all treated participants. CR=Disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of spleen, liver, and bone marrow involvement. PR=Regression of measurable disease and no new sites; no increase in size of liver or spleen. >=50% decrease in SPD of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions)
Time Frame	From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Measure Participants	92
Number (95% Confidence Interval) [Percentage of participants]	4.3 4.7%

2. Secondary Outcome

Title	Duration of Response (DOR) Based on IRRC Assessments
Description	DOR is defined as the time from first remission (CR or PR) to the date of initial objectively documented progression as determined using the revised International Working Group Criteria for non-Hodgkin Lymphoma, or death due to any cause, whichever occurs first. CR definition includes the complete disappearance of all evidence of disease, the definition of PR includes at least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses, and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir, as described in the IWG response criteria
Time Frame	From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Measure Participants	92
Median (95% Confidence Interval) [months]	10.94

3. Secondary Outcome

Title	Complete Remission Rate (CRR) Based on IRRC Assessment
Description	CRR is defined as the number of subjects with a BOR of CR according to the revised International Working Group Criteria for non-Hodgkin Lymphoma, divided by the number of treated participants and expressed as a percentage. CR=Disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of spleen, liver, and bone marrow involvement.
Time Frame	From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Measure Participants	92
Number (95% Confidence Interval) [Percentage of participants]	1.1 1.2%

4. Secondary Outcome

Title	Partial Remission (PR) Rate Based on IRRC Assessment
Description	PR rate is defined as the number of participants with a best overall response (BOR) of PR according to the 2007 International Working Group (IWG) criteria, based on IRRC assessment, divided by the number of treated participants and expressed as a percentage. PR=Regression of measurable disease and no new sites; no increase in size of liver or spleen. >=50% decrease in SPD of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions)
Time Frame	From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Measure Participants	92
Number (95% Confidence Interval) [Percentage of participants]	3.3 3.6%

5. Secondary Outcome

Title	Progression Free Survival (PFS) Based on IRRC Assessment
Description	PFS was summarized descriptively using the Kaplan-Meier (KM) product-limit method. Median values of PFS, along with the two-sided 95% CIs were calculated using a method based on log-log transformation.
Time Frame	From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Measure Participants	92
Median (95% Confidence Interval) [months]	2.20

6. Secondary Outcome

Title	Overall Response Rate (ORR) Based on Investigator Assessments
Description	ORR is determined by investigator assessments according to the revised International Working Group Criteria for non-Hodgkin Lymphoma. ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) and is expressed as a percentage of all treated participants. CR=Disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of spleen, liver, and bone marrow involvement. PR=Regression of measurable disease and no new sites; no increase in size of liver or spleen. >=50% decrease in SPD of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions)
Time Frame	From Week 9 until documented disease progression or study discontinuation (assessed up to June 2017, approximately 38 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm 1: Nivolumab
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
Measure Participants	92
Number (95% Confidence Interval) [Percentage of participants]	10.9 11.8%

Adverse Events

Time Frame	AEs collected were reported between first dose and 100 days after last dose of study therapy (up to approximately 6 years 9 months)
Arm/Group Title	Nivolumab 3 mg/kg
Arm/Group Description	Nivolumab 3mg/kg intravenously every 2 weeks until disease progression or discontinuation due to toxicity
All Cause Mortality
	Nivolumab 3 mg/kg
	Affected / at Risk (%)	# Events
Total	36/92 (39.1%)
Serious Adverse Events
	Nivolumab 3 mg/kg
	Affected / at Risk (%)	# Events
Total	46/92 (50%)
Blood and lymphatic system disorders
Autoimmune haemolytic anaemia	1/92 (1.1%)
Cytopenia	1/92 (1.1%)
Febrile neutropenia	4/92 (4.3%)
Pancytopenia	1/92 (1.1%)
Cardiac disorders
Cardiac failure	1/92 (1.1%)
Cardiac failure acute	1/92 (1.1%)
Cardiac failure congestive	1/92 (1.1%)
Myocardial infarction	1/92 (1.1%)
Gastrointestinal disorders
Abdominal discomfort	1/92 (1.1%)
Abdominal pain	3/92 (3.3%)
Ascites	1/92 (1.1%)
Colitis	1/92 (1.1%)
Constipation	1/92 (1.1%)
Diarrhoea	3/92 (3.3%)
Diverticulum intestinal haemorrhagic	1/92 (1.1%)
Dysphagia	1/92 (1.1%)
Gastrointestinal pain	1/92 (1.1%)
Intestinal obstruction	1/92 (1.1%)
Pancreatitis acute	1/92 (1.1%)
Small intestinal obstruction	1/92 (1.1%)
Vomiting	1/92 (1.1%)
General disorders
Asthenia	1/92 (1.1%)
Fatigue	1/92 (1.1%)
General physical health deterioration	1/92 (1.1%)
Multiple organ dysfunction syndrome	1/92 (1.1%)
Pyrexia	6/92 (6.5%)
Immune system disorders
Anaphylactic shock	1/92 (1.1%)
Hypersensitivity	1/92 (1.1%)
Infections and infestations
Appendicitis	1/92 (1.1%)
Bacteraemia	2/92 (2.2%)
Erysipelas	1/92 (1.1%)
Fungal infection	1/92 (1.1%)
Herpes zoster	2/92 (2.2%)
Lower respiratory tract infection	3/92 (3.3%)
Pneumonia	2/92 (2.2%)
Pulmonary sepsis	1/92 (1.1%)
Pyelonephritis	1/92 (1.1%)
Skin infection	2/92 (2.2%)
Staphylococcal sepsis	1/92 (1.1%)
Urinary tract infection	1/92 (1.1%)
Viral infection	1/92 (1.1%)
Injury, poisoning and procedural complications
Infusion related reaction	1/92 (1.1%)
Investigations
Influenza B virus test positive	1/92 (1.1%)
Transaminases increased	1/92 (1.1%)
Metabolism and nutrition disorders
Dehydration	1/92 (1.1%)
Hypercalcaemia	1/92 (1.1%)
Hyperglycaemia	2/92 (2.2%)
Hypokalaemia	1/92 (1.1%)
Musculoskeletal and connective tissue disorders
Bone pain	1/92 (1.1%)
Muscular weakness	1/92 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma	1/92 (1.1%)
Malignant neoplasm progression	8/92 (8.7%)
Myelodysplastic syndrome	1/92 (1.1%)
Squamous cell carcinoma	1/92 (1.1%)
Nervous system disorders
Sciatica	1/92 (1.1%)
Syncope	1/92 (1.1%)
Psychiatric disorders
Confusional state	1/92 (1.1%)
Renal and urinary disorders
Acute kidney injury	1/92 (1.1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/92 (1.1%)
Aspiration	1/92 (1.1%)
Dyspnoea	1/92 (1.1%)
Immune-mediated pneumonitis	1/92 (1.1%)
Pleural effusion	2/92 (2.2%)
Pneumonitis	1/92 (1.1%)
Respiratory failure	1/92 (1.1%)
Skin and subcutaneous tissue disorders
Erythema multiforme	1/92 (1.1%)
Rash	1/92 (1.1%)
Toxic epidermal necrolysis	1/92 (1.1%)
Other (Not Including Serious) Adverse Events
	Nivolumab 3 mg/kg
	Affected / at Risk (%)	# Events
Total	89/92 (96.7%)
Blood and lymphatic system disorders
Anaemia	15/92 (16.3%)
Neutropenia	10/92 (10.9%)
Thrombocytopenia	8/92 (8.7%)
Gastrointestinal disorders
Abdominal pain	15/92 (16.3%)
Constipation	14/92 (15.2%)
Diarrhoea	22/92 (23.9%)
Dysphagia	5/92 (5.4%)
Nausea	23/92 (25%)
Vomiting	12/92 (13%)
General disorders
Asthenia	9/92 (9.8%)
Fatigue	23/92 (25%)
Oedema peripheral	10/92 (10.9%)
Pyrexia	25/92 (27.2%)
Infections and infestations
Nasopharyngitis	8/92 (8.7%)
Pneumonia	6/92 (6.5%)
Upper respiratory tract infection	11/92 (12%)
Urinary tract infection	9/92 (9.8%)
Metabolism and nutrition disorders
Decreased appetite	14/92 (15.2%)
Hypokalaemia	6/92 (6.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/92 (6.5%)
Back pain	11/92 (12%)
Muscle spasms	5/92 (5.4%)
Myalgia	6/92 (6.5%)
Nervous system disorders
Dizziness	7/92 (7.6%)
Headache	5/92 (5.4%)
Respiratory, thoracic and mediastinal disorders
Cough	25/92 (27.2%)
Dyspnoea	13/92 (14.1%)
Oropharyngeal pain	5/92 (5.4%)
Skin and subcutaneous tissue disorders
Pruritus	11/92 (12%)
Rash	8/92 (8.7%)
Skin lesion	5/92 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.