Testing Nivolumab to Prevent Disease From Coming Back After Treatment in Patients With Acute Myeloid Leukemia, REMAIN Trial

Acute Myeloid Leukemia Clinical Trial

Official title:

Randomized Phase II Study to Assess the Role of Nivolumab as Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients After Chemotherapy (REMAIN TRIAL)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02275533
• Other study ID #: NCI-2014-02167
• Secondary ID: NCI-2014-02167CI
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 2, 2015
• Est. completion date: August 31, 2024

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well nivolumab works in eliminating any remaining cancer cells and preventing cancer from returning in patients with acute myeloid leukemia that had a decrease in or disappearance of signs and symptoms of cancer after receiving chemotherapy. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Description:

PRIMARY OBJECTIVE:

I. To evaluate and compare the progression free survival rate after randomization in the two treatment arms (nivolumab versus [vs.] observation).

SECONDARY OBJECTIVES:

I. To determine and compare the overall survival rates in the two arms. II. To determine and compare the incidence of non-relapse mortality in the two arms.

III. To evaluate the toxicities of nivolumab as maintenance.

EXPLORATORY OBJECTIVES:

I. To analyze PD-L1 expression on acute myeloid leukemia (AML) cells from peripheral blood and/or bone marrow samples at diagnosis if available and at the time of study enrollment.

II. To monitor AML minimal residual disease (MRD) by Wilms tumor 1 (WT1) polymerase chain reaction (PCR) at enrollment and at subsequent defined time points in the nivolumab-treated and control groups.

III. To perform an exploratory analysis on the frequencies, absolute numbers and subsets of T cells (including regulatory T cells) in the nivolumab-treated and control groups with an emphasis on activation markers.

IV. To perform deep sequencing of T cell receptor (TCR)-alpha and TCR-beta chains on polyclonal T cells at baseline and at subsequent time points in the nivolumab and control groups.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes once every 2 weeks. Treatment repeats every 2 weeks for 46 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy at screening, months 3, 6, and 12, as clinically indicated, and at the time off study. Patients also undergo collection of blood samples at screening, weeks 9, 13, 25, and 53, and during off-study evaluation or at time of clinically suspected relapse. Patients may undergo echocardiography (ECHO) as clinically indicated.

ARM II: Patients undergo standard of care clinical observation for up to 2 years. Upon disease relapse, patients may cross-over to Arm I. Patients also undergo bone marrow biopsy at screening, months 3, 6, and 12, as clinically indicated, and during off-study evaluation. Patients also undergo collection of blood samples at screening, weeks 9, 13, 25, and 53, and during off-study evaluation or at time of clinically suspected relapse. Patients may undergo ECHO as clinically indicated.

After completion of study treatment, patients are followed up periodically for 2 years, every 6 months for 1 year, and then yearly thereafter.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 82
• Est. completion date: August 31, 2024
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• AML patients in first complete remission (CR) (CR1) or first complete remission with incomplete blood count recovery (CRi) after induction and/or consolidation chemotherapy; except young (< 60 years) AML patients in European LeukemiaNet favorable group; (Since young AML patients in the European LeukemiaNet favorable group have excellent 2 year progression free survival [PFS] at around 64%, further maintenance therapy might not provide additional benefit; thus the current trial will exclude young favorable group AML patients), patients could receive any cycle consolidation or no consolidation per the discretion by the treating physician

• Within 60 days after bone marrow biopsy confirmed remission after the patients recover from their last course of chemotherapy, the goal to consent the eligible patient prior to the remission confirmation bone marrow biopsy at the end of the planned chemotherapy); ideally, the research samples will be collected during the bone marrow biopsy, and the patient will be enrolled to the study within 2 weeks of the bone marrow biopsy; if there is delay to enroll the patient after the bone marrow biopsy and research sample collection, it is ok not to repeat bone marrow biopsy within 4 weeks, after the last bone marrow biopsy, if there is no sign of disease relapse; a repeat bone marrow biopsy should be done if the delay of enrollment is more than 4 weeks after the last bone marrow biopsy; patients with confirmed remission within 60 days after the last bone marrow biopsy, without research samples collection, should have a repeat bone marrow biopsy conducted within two weeks prior to enrolling on the study

• Patient is not a candidate for stem cell transplant due to advanced age or co-morbidities; or the enrollee does not have donor available; or the enrollee declines stem cell transplant due to personal belief; or stem cell transplant is not standard of care based on the risk category of disease

• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of nivolumab in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

• Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0 or 1 (Karnofsky >= 70%)

• Life expectancy of greater than 6 months

• Leukocytes >= 1,500/mcL

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 50,000/mcL or recovery to the baseline count

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN

• Amylase and lipase =< 1.5 x ULN without any symptoms of pancreatitis

• Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)

• The effects of nivolumab on the developing human fetus are unknown; for this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; WOCBP should use an adequate method to avoid pregnancy for 23 weeks after the last dose of investigational drug nivolumab; women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab; women must not be breastfeeding; men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception

• Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

• WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 23 weeks after the last dose of investigational product; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; these durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days

• Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (AEs) due to agents administered more than 4 weeks earlier

• Patients who are receiving any other investigational agents

• Patients should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways

• Patients with known central nervous system (CNS) involvement may be excluded because of poor prognosis and concerns regarding progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; however, if CNS disease is cleared before the treatment with nivolumab, patients could be allowed if no permanent CNS damage

• History of severe hypersensitivity reaction to any monoclonal antibody

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study because nivolumab is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, breastfeeding should be discontinued if the mother is treated with nivolumab

• Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) might be enrolled if the viral load by PCR is undetectable with/without active treatment and absolute lymphocyte count >= 350/ul

• Patients with a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute or chronic infection might be enrolled if the viral load by PCR is undetectable with/without active treatment

• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible

• 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)

• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications 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; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted

• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Bone Marrow Biopsy
Undergo bone marrow biopsy

Other:
• Clinical Observation
Undergo standard of care clinical observation

Procedure:
• Echocardiography
Undergo ECHO

Biological:
• Nivolumab
Given IV

Locations

Country	Name	City	State
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	NCI - Center for Cancer Research	Bethesda	Maryland
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Case Western Reserve University	Cleveland	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	University of Kansas Clinical Research Center	Fairway	Kansas
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Ben Taub General Hospital	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Smilow Cancer Center/Yale-New Haven Hospital	New Haven	Connecticut
United States	Yale University	New Haven	Connecticut
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Moffitt Cancer Center	Tampa	Florida
United States	Moffitt Cancer Center-International Plaza	Tampa	Florida
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival (PFS)	Kaplan-Meier plots will be used to estimate PFS in each arm and a stratified log rank test will be performed to compare the two groups. In addition, Cox proportional hazards models will be fit to provide estimates of the hazard ratio (HR) and associated 95% confidence interval (CIs), both unadjusted and adjusted for baseline covariates. Descriptive, subset analysis of PFS will be performed for minimal residual disease (MRD) positive patients.	Time from randomization to disease relapse or death from any cause, assessed up to 2 years post-treatment
Secondary	Overall survival (OS)	For overall survival, Kaplan-Meier plots will be generated for each treatment arm and the curves will be compared using a log rank test. Kaplan-Meier estimates with 95% CI will be summarized every 6 months using Greenwood's formula for the standard error of the Kaplan-Meier estimate. In addition to the Kaplan-Meier estimates, Cox proportional hazards models will be fit to estimate HRs and to assess and adjust for the effects of covariates. Descriptive, subset analysis of OS will be performed for MRD negative patients.	Time from randomization to the date of death from any cause, assessed up to 2 years post-treatment
Secondary	Non-relapse mortality (NRM)	NRM will be analyzed using competing risks models with deaths due to relapse as a competing risk. Cumulative incidence curves will be generated and treatment effects summarized using the sub-distribution hazard ratio with and without adjustment for covariates	Duration between the date of randomization and the date of patient death due to reasons other than relapse, assessed up to 2 years post-treatment
Secondary	Incidence of adverse effects of nivolumab	Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Summary tables for adverse events (AEs) will include only AEs that started or worsened after randomization. The incidence of treatment-related adverse events (new or worsening from baseline after randomization) will be summarized by system organ class and/ or preferred term, severity (based on CTCAE grades), type of adverse event, and relation to study treatment by treatment group. Toxicity rates will be compared between the two treatment arms via chi-squares or Fisher's exact tests.	Up to 100 days post-treatment