Clinical Trials /

Nivolumab in Eliminating Minimal Residual Disease and Preventing Relapse in Patients With Acute Myeloid Leukemia in Remission After Chemotherapy

NCT02275533

Description:

This randomized 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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab in Eliminating Minimal Residual Disease and Preventing Relapse in Patients With Acute Myeloid Leukemia in Remission After Chemotherapy
  • 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 IDs

  • ORG STUDY ID: NCI-2014-02167
  • SECONDARY ID: NCI-2014-02167
  • SECONDARY ID: CIRB 15-0185
  • SECONDARY ID: CVCIRB 15-0185
  • SECONDARY ID: 9706
  • SECONDARY ID: 9706
  • SECONDARY ID: N01CM00071
  • SECONDARY ID: P30CA014599
  • SECONDARY ID: UM1CA186644
  • SECONDARY ID: UM1CA186686
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186691
  • SECONDARY ID: UM1CA186712
  • SECONDARY ID: UM1CA186717
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT02275533

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (nivolumab)

Purpose

This randomized 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.

Detailed Description

      PRIMARY OBJECTIVES:

      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 programmed cell death (PD)-ligand (L)1 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 60 minutes once every 2 weeks.
      Treatment repeats every 2 weeks for 46 courses in the absence of disease progression or
      unacceptable toxicity.

      ARM II: Patients undergo standard of care clinical observation for up to 2 years. Upon
      disease relapse, patients may cross-over to Arm I.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (nivolumab)ExperimentalPatients receive nivolumab IV over 60 minutes once every 2 weeks. Treatment repeats every 2 weeks for 46 courses in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
Arm II (observation)Active ComparatorPatients undergo standard of care clinical observation for up to 2 years. Upon disease relapse, patients may cross-over to Arm I.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  AML patients in first complete remission (CR) (CR1) or first complete remission with
                 incomplete blood count recovery (CRi) after induction and consolidation chemotherapy;
                 except young (< 60 years) AML patients in European LeukemiaNet favorable group; (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 will be 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
    
              -  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-programmed
                 cell death protein 1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), anti-PD-L2,
                 anti-cytotoxic T-lymphocyte-associated protein 4 (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 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 should be
                 evaluated for the potential need for additional treatment before coming on study
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression free survival (PFS)
    Time Frame:Time from randomization to disease relapse or death from any cause, assessed up to 2 years post-treatment
    Safety Issue:
    Description: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.

    Secondary Outcome Measures

    Measure:Overall survival (OS)
    Time Frame:Time from randomization to the date of death from any cause, assessed up to 2 years post-treatment
    Safety Issue:
    Description: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.
    Measure:Non-relapse mortality (NRM)
    Time Frame: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
    Safety Issue:
    Description: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
    Measure:Incidence of adverse effects of nivolumab
    Time Frame:Up to 100 days post-treatment
    Safety Issue:
    Description: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.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    November 26, 2019