Testing Nivolumab as a Potential Targeted Treatment in Cancers With Mismatch Repair Deficiency (MATCH-Subprotocol Z1D)

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT04439214
• Collaborator: (none)
• Enrollment: 47
• Location: 1
• Arm: 1
• Actual Duration (Months): 47.5
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This phase II MATCH treatment trial identifies the effects of nivolumab in patients whose cancer has a genetic change called mismatch repair deficiency. Mismatch repair deficiency refers to cells that have mutations (changes) in certain genes that are involved in correcting mistakes made when DNA is copied in a cell. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells with mismatch repair deficiency to grow and spread. Researchers hope to learn if nivolumab will shrink this type of cancer or stop its growth.

Condition or Disease	Intervention/Treatment	Phase
Advanced Lymphoma; Advanced Malignant Solid Neoplasm; Hematopoietic and Lymphoid Cell Neoplasm; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Plasma Cell Myeloma	Biological: Nivolumab	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.

SECONDARY OBJECTIVES:

1. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.

2. To evaluate time until death or disease progression.

EXPLORATORY OBJECTIVES:

1. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.

2. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, and then every 6 months for year 3 from study entry.

THE MATCH SCREENING TRIAL:

Please see NCT02465060 for information on the MATCH Screening Protocol and applicable documents.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MATCH Treatment Subprotocol Z1D: Nivolumab in Patients With Tumors With Mismatch Repair Deficiency
• Actual Study Start Date: May 31, 2016
• Actual Primary Completion Date: Oct 11, 2018
• Actual Study Completion Date: May 17, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (nivolumab) Patients receive nivolumab IV over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Biological: Nivolumab; Given IV; Other Names: BMS-936558 MDX-1106 NIVO ONO-4538 Opdivo

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [assessed at baseline, then every 8 weeks for the first 2 years, then every 12 weeks in year 3, until disease progression]

   Overall response rate was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) among all eligible and treated patients. Best overall response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. The 90% two-sided binomial exact confidence interval was calculated for ORR.

Secondary Outcome Measures

1. 6-month Progression-free Survival (PFS) Rate [assessed at baseline, then every 8 weeks for the first 2 years, then every 12 weeks in year 3, until disease progression]

   PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. The 6-month PFS rate was estimated using the Kaplan-Meier method which can provide a point estimate for any specific time point. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.

2. Progression-free Survival (PFS) [assessed at baseline, then every 8 weeks for the first 2 years, then every 12 weeks in year 3, until disease progression]

   PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol

• Patients must have mismatch repair deficiency as determined via the MATCH Master Protocol

• Women of childbearing potential (WOCBP) receiving nivolumab must agree to use adequate contraception (hormonal or double barrier method of birth control; abstinence) from one week prior to study treatment starting, during treatment, and for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP must agree to use adequate contraception (hormonal or double barrier method of birth control; abstinence) from one week prior to study treatment starting, during treatment, and for a period of 7 months after the last dose of nivolumab

• Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection may be eligible provided they have the following:

• There must be no evidence of clinically significant hepatic injury from hepatitis virus infection

• For HBV, patients must be on suppressive therapy and have undetectable HBV viral load

• For HCV, patients must either be on suppressive therapy for HCV or have already completed therapy thought to have eradicated HCV

Exclusion Criteria:

• Patients must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition

• No prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40 or anti-CTLA-4 antibodies (or any other antibody targeting T cell co-regulatory pathways)

• Patients with cancers for which nivolumab is approved or becomes approved are excluded (e.g: colorectal cancer, locally advanced or metastatic urothelial carcinoma, unresectable or metastatic melanoma, metastatic non-small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin lymphoma, and recurrent or metastatic squamous cancer of the head and neck)

• Must not have received any of the following therapies within four weeks prior to the first dose of the study drug: IL-2, interferon, or other non-study immunotherapy regimens or immunosuppressive agents

• Must not have a history of toxic epidermal necrolysis (Stevens-Johnson syndrome)

• Must not have received growth factors, including but not limited to granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin, etc. within 2 weeks of study drug administration. Use of such agents while on study is also prohibited. Prior use of growth factors should be documented in the patient's medical history

• Must not have a history of any autoimmune disease: inflammatory bowel disease, (including ulcerative colitis and Crohn's disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus (SLE) autoimmune vasculitis (e.g., Wegener's Granulomatosis), central nervous system (CNS) or motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre syndrome, myasthenia gravis, multiple sclerosis). Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event). Entry of patients with autoimmune diagnoses not listed here must be approved by the protocol chair

• Must not be on supplemental home oxygen

• Must not have evidence of interstitial lung disease

• Patients with a requirement for steroid treatment or other immunosuppressive treatment: Patients will be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease

• No history of severe hypersensitivity reaction to any monoclonal antibody

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ECOG-ACRIN Cancer Research Group	Philadelphia	Pennsylvania	United States	19103

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Nilofer S Azad, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

• Study Protocol - Oct 12, 2018

More Information

Additional Information:

• Journal of Clinical Oncology, Volume 38, Issue 3

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04439214
• Other Study ID Numbers: NCI-2020-03172; NCI-2020-03172; EAY131-Z1D; EAY131-Z1D; U10CA180820; U24CA196172
• First Posted: Jun 19, 2020
• Last Update Posted: Apr 6, 2021
• Last Verified: Mar 1, 2021

• Keywords provided by National Cancer Institute (NCI): Nivolumab; Lymphoma; Mismatch repair deficiency
• Additional relevant MeSH terms: Lymphoma; Neoplasms; Multiple Myeloma; Neoplasms, Plasma Cell; Nivolumab

Study Results

Participant Flow

Recruitment Details	Subprotocol Z1D was activated in NCI-MATCH on May 31, 2016. Patients enrolled for screening by the MATCH assay between this date and the end of screening enrollment in May 2017, were evaluated for MSH2 and MLH1 expression by immunohistochemistry (IHC). In the end, 47 patients were enrolled to the subprotocol.
Pre-assignment Detail	To be assigned to a specific MATCH subprotocol, patients needed to submit a tumor biopsy for molecular characterization and those with molecular variants addressed by treatments included in the trial entered corresponding MATCH subprotocol. For the subprotocol Z1D, patients had to have complete loss of nuclear expression of MLH1 or MSH2 MMR gene products by IHC.

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV
Period Title: Overall Study
STARTED	47
Eligible	42
Treated	47
Treated and Reported Adverse Event Data	46
Eligible and Treated	42
COMPLETED	0
NOT COMPLETED	47

Baseline Characteristics

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV
Overall Participants	42
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.5
Sex: Female, Male (Count of Participants)
Female	28 66.7%
Male	14 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4.8%
Not Hispanic or Latino	40 95.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 4.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 9.5%
White	35 83.3%
More than one race	0 0%
Unknown or Not Reported	1 2.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) among all eligible and treated patients. Best overall response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. The 90% two-sided binomial exact confidence interval was calculated for ORR.
Time Frame	assessed at baseline, then every 8 weeks for the first 2 years, then every 12 weeks in year 3, until disease progression

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV
Measure Participants	42
Number (90% Confidence Interval) [percentage of participants]	35.7 85%

2. Secondary Outcome

Title	6-month Progression-free Survival (PFS) Rate
Description	PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. The 6-month PFS rate was estimated using the Kaplan-Meier method which can provide a point estimate for any specific time point. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.
Time Frame	assessed at baseline, then every 8 weeks for the first 2 years, then every 12 weeks in year 3, until disease progression

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV
Measure Participants	42
Number (90% Confidence Interval) [percentage of participants]	51.3 122.1%

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.
Time Frame	assessed at baseline, then every 8 weeks for the first 2 years, then every 12 weeks in year 3, until disease progression

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV
Measure Participants	42
Median (90% Confidence Interval) [months]	6.3

Adverse Events

Time Frame	Assessed every 28 days while on treatment and for 30 days after the end of treatment, up to 3 years
Adverse Event Reporting Description	All the 47 enrolled patients started protocol therapy and followed for survival, but 1 patient had disease progression in cycle 1 and adverse event data were not reported. So adverse events were reported for the 46 patients who reported adverse event data, and all-cause mortality was reported for the 47 patients.
Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 30-60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Nivolumab)
	Affected / at Risk (%)	# Events
Total	24/47 (51.1%)
Serious Adverse Events
	Treatment (Nivolumab)
	Affected / at Risk (%)	# Events
Total	20/46 (43.5%)
Blood and lymphatic system disorders
Anemia	8/46 (17.4%)
Gastrointestinal disorders
Nausea	1/46 (2.2%)
Vomiting	1/46 (2.2%)
General disorders
Fatigue	2/46 (4.3%)
Infections and infestations
Sepsis	2/46 (4.3%)
Skin infection	2/46 (4.3%)
Injury, poisoning and procedural complications
Fall	1/46 (2.2%)
Investigations
Alanine aminotransferase increased	1/46 (2.2%)
Alkaline phosphatase increased	1/46 (2.2%)
Creatinine increased	2/46 (4.3%)
Ejection fraction decreased	1/46 (2.2%)
Weight gain	1/46 (2.2%)
Metabolism and nutrition disorders
Dehydration	3/46 (6.5%)
Hyperglycemia	2/46 (4.3%)
Hypocalcemia	1/46 (2.2%)
Hypokalemia	1/46 (2.2%)
Hyponatremia	1/46 (2.2%)
Musculoskeletal and connective tissue disorders
Back pain	1/46 (2.2%)
Flank pain	1/46 (2.2%)
Generalized muscle weakness	1/46 (2.2%)
Nervous system disorders
Encephalopathy	1/46 (2.2%)
Myelitis	1/46 (2.2%)
Renal and urinary disorders
Acute kidney injury	1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/46 (2.2%)
Pleural effusion	1/46 (2.2%)
Pneumonitis	1/46 (2.2%)
Skin and subcutaneous tissue disorders
Pruritus	2/46 (4.3%)
Rash maculo-papular	3/46 (6.5%)
Surgical and medical procedures
Surgical and medical procedures - Other, specify	1/46 (2.2%)
Vascular disorders
Hypotension	1/46 (2.2%)
Peripheral ischemia	1/46 (2.2%)
Other (Not Including Serious) Adverse Events
	Treatment (Nivolumab)
	Affected / at Risk (%)	# Events
Total	40/46 (87%)
Blood and lymphatic system disorders
Anemia	12/46 (26.1%)
Endocrine disorders
Hyperthyroidism	7/46 (15.2%)
Hypothyroidism	7/46 (15.2%)
Gastrointestinal disorders
Diarrhea	6/46 (13%)
Nausea	6/46 (13%)
General disorders
Edema limbs	3/46 (6.5%)
Fatigue	21/46 (45.7%)
Investigations
Alanine aminotransferase increased	3/46 (6.5%)
Alkaline phosphatase increased	4/46 (8.7%)
Aspartate aminotransferase increased	6/46 (13%)
Creatinine increased	3/46 (6.5%)
Lymphocyte count decreased	6/46 (13%)
Platelet count decreased	6/46 (13%)
White blood cell decreased	3/46 (6.5%)
Investigations - Other, specify	3/46 (6.5%)
Metabolism and nutrition disorders
Anorexia	7/46 (15.2%)
Hyperglycemia	3/46 (6.5%)
Hypoalbuminemia	8/46 (17.4%)
Hypomagnesemia	7/46 (15.2%)
Hyponatremia	4/46 (8.7%)
Metabolism and nutrition disorders - Other, specify	3/46 (6.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/46 (10.9%)
Generalized muscle weakness	3/46 (6.5%)
Myalgia	3/46 (6.5%)
Nervous system disorders
Dizziness	4/46 (8.7%)
Respiratory, thoracic and mediastinal disorders
Cough	4/46 (8.7%)
Dyspnea	4/46 (8.7%)
Skin and subcutaneous tissue disorders
Pruritus	7/46 (15.2%)
Rash maculo-papular	8/46 (17.4%)
Vascular disorders
Hot flashes	4/46 (8.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.