Clinical Trials /

Nivolumab and Ipilimumab After Donor Stem Cell Transplant in Treating Patients With High Risk Refractory or Relapsed Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT03600155

Description:

This phase Ib trial studies the side effects and best dose of nivolumab and ipilimumab after donor stem cell transplant in treating patients with high risk acute myeloid leukemia or myelodysplastic syndrome that does not respond to treatment or has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, 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:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Ipilimumab After Donor Stem Cell Transplant in Treating Participants With High Risk Refractory or Relapsed Acute Myeloid Leukemia
  • Official Title: A Phase I Study of Nivolumab in Combination With Ipilimumab for the Treatment of Patients With High Risk or Refractory/Relapsed Acute Myeloid Leukemia Following Allogeneic Stem Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 2017-0349
  • SECONDARY ID: NCI-2018-01450
  • SECONDARY ID: 2017-0349
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03600155

Conditions

  • Allogeneic Hematopoietic Stem Cell Transplantation Recipient
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm B (ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (nivolumab)

Purpose

This phase I trial studies the side effects and best dose of nivolumab and ipilimumab after donor stem cell transplant in treating participants with high risk acute myeloid leukemia that does not respond to treatment or has come back. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of cancer cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of
      nivolumab and ipilimumab alone and in combination in patients with high risk or
      refractory/relapsed acute myeloid leukemia (AML) following allogeneic stem cell
      transplantation (allo-SCT).

      II. To evaluate the toxicity of nivolumab and ipilimumab alone and in combination with regard
      to the rate and severity of acute graft versus host disease (aGVHD).

      SECONDARY OBJECTIVES:

      I. To determine the overall response rate (ORR) of nivolumab, ipilimumab and the combination
      in patients with high risk or refractory/ relapsed AML following allo-SCT.

      II. To determine the duration of response, disease-free survival (DFS), and overall survival
      (OS) of patients with high risk or refractory/ relapsed AML treated with this combination
      following allo-SCT.

      EXPLORATORY OBJECTIVES:

      I. To identify neo-antigens, the immune cell phenotype, expression of immune checkpoint
      molecules and the T cell receptor (TCR) repertoire following treatment with nivolumab,
      ipilimumab and the combination.

      II. To study immunological and molecular changes in the peripheral blood and bone marrow in
      response to nivolumab and ipilimumab.

      III. To investigate the TCR repertoire and immune phenotype in patients who experience aGVHD.

      OUTLINE: This is a dose-escalation study. Participants are assigned to 1 of 3 arms.

      ARM A: Beginning at least 6 weeks post-stem cell transplant, participants receive nivolumab
      intravenously (IV) over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up
      to 6 courses in the absence of disease progression or unacceptable toxicity.

      ARM B: Beginning at least 6 weeks post-stem cell transplant, participants receive ipilimumab
      IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the
      absence of disease progression or unacceptable toxicity.

      ARM C: Beginning at least 6 weeks post-stem cell transplant, participants receive nivolumab
      IV over 60 minutes on days 1, 14, and 28, and ipilimumab IV over 90 minutes on day 1.
      Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, participants are followed up within 30 days and
      periodically thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (nivolumab)ExperimentalBeginning at least 6 weeks post-stem cell transplant, participants receive nivolumab IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
    Arm B (ipilimumab)ExperimentalBeginning at least 6 weeks post-stem cell transplant, participants receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
      Arm C (nivolumab and ipilimumab)ExperimentalBeginning at least 6 weeks post-stem cell transplant, participants receive nivolumab IV over 60 minutes on days 1, 14, and 28, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

        Eligibility Criteria

                Inclusion Criteria:
        
                  -  Patients with morphologic/histologic evidence of relapsed or refractory AML following
                     allogeneic stem cell transplantation
        
                  -  Patients must have received preparative regimens to include either
                     fludarabine/busulfan (area under curve [AUC] >= 5000)/post cyclophosphamide or
                     fludarabine/melphalan (100 or 140)/post cyclophosphamide
        
                  -  Patient must have achieved myeloid engraftment as defined by an absolute neutrophil
                     count >= 500 micro/L on 3 consecutive days
        
                  -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2
        
                  -  Total bilirubin =< 2 times upper limit of normal (x ULN) (=< 3 x ULN if considered to
                     be due to Gilbert's syndrome)
        
                  -  Aspartate aminotransferase or alanine aminotransferase =< 2.5 x ULN
        
                  -  Serum creatinine =< 2 x ULN or glomerular filtration rate (GFR) >= 50
        
                  -  Patients must provide written informed consent
        
                  -  The interval from the infusion of stem cells to time of initiation of nivolumab or
                     ipilimumab will be at least 6 weeks (42 days)
        
                  -  Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
                     at least 12 months) or if of childbearing potential, must have a negative serum or
                     urine pregnancy test within 72 hours before the start of the treatment
        
                  -  Women of childbearing potential must agree to use an adequate method of contraception
                     during the study and until 3 months after the last treatment. Males must be surgically
                     or biologically sterile or agree to use an adequate method of contraception during the
                     study until 3 months after the last treatment
        
                  -  Fully matched related donor
        
                Exclusion Criteria:
        
                  -  Patients with known allergy or hypersensitivity to nivolumab or ipilimumab or any of
                     their components
        
                  -  Patients with acute GVHD > grade 2 at any time during the post-transplant course
        
                  -  Patients with a known history of severe interstitial lung disease or severe
                     pneumonitis or active pneumonitis that is uncontrolled in the opinion of the treating
                     physician
        
                  -  Patients with a known history of any of the following autoimmune diseases are
                     excluded:
        
                       -  Patients with a history of inflammatory bowel disease (including Crohn's disease
                          and ulcerative colitis)
        
                       -  Patients with a history of rheumatoid arthritis, systemic progressive sclerosis
                          (scleroderma), systemic lupus erythematosus, autoimmune vasculitis (e.g.,
                          Wegener's granulomatosis)
        
                  -  Patients with solid organ allografts (such as renal transplant) are excluded
        
                  -  Ongoing immunosuppressive therapy for the treatment of GVHD. Patients receiving GVHD
                     prophylaxis will be allowed on this study
        
                  -  Patients with symptomatic central nervous system (CNS) leukemia at the time of
                     evaluation or patients with poorly controlled CNS leukemia
        
                  -  Active and uncontrolled disease/(active uncontrolled infection, uncontrolled
                     hypertension despite adequate medical therapy, active and uncontrolled congestive
                     heart failure New York Heart Association [NYHA] class III/IV, clinically significant
                     and uncontrolled arrhythmia) as judged by the treating physician
        
                  -  Patients with known human immunodeficiency virus seropositivity will be excluded
        
                  -  Known to be positive for hepatitis B by surface antigen expression. Known to have
                     active hepatitis C infection (positive by polymerase chain reaction or on antiviral
                     therapy for hepatitis C within the last 6 months)
        
                  -  Any other medical, psychological, or social condition that may interfere with study
                     participation or compliance, or compromise patient safety in the opinion of the
                     investigator
        
                  -  Patients unwilling or unable to comply with the protocol
        
                  -  Pregnant or breastfeeding
              
        Maximum Eligible Age:N/A
        Minimum Eligible Age:18 Years
        Eligible Gender:All
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Optimal dose of nivolumab in combination with ipilimumab
        Time Frame:Up to day 42
        Safety Issue:
        Description:Dose-finding will be carried out using the Bayesian optimal interval design (BOIN).

        Secondary Outcome Measures

        Measure:Overall response rate (ORR)
        Time Frame:Up to 1 year
        Safety Issue:
        Description:ORR will be estimated as the proportion of patients who achieve complete response (CR), complete response with incomplete bone marrow recovery (CRi), or partial response (PR). The 2-sided 95% exact binomial confidence interval (CI) of ORR will be calculated.
        Measure:Duration of response (DOR)
        Time Frame:From the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, assessed up to 1 year
        Safety Issue:
        Description:DOR will be estimated using the method of Kaplan and Meier, and distributions will be compared using the log-rank test.
        Measure:Disease-free survival (DFS)
        Time Frame:From the date of first dose of study drug until the date of documented graft versus host disease (GVHD), relapses from CR, or death from any cause, assessed up to 1 year
        Safety Issue:
        Description:DFS defined as the number of days from the date of first dose of study drug until the date of documented GVHD, relapses from CR, or death from any cause, whichever occurs first.
        Measure:Overall survival (OS)
        Time Frame:From the first dose of study drug until death or last follow-up, assessed up to 1 year
        Safety Issue:
        Description:OS defined as the time from the first dose of study drug until death or last follow-up.

        Details

        Phase:Phase 1
        Primary Purpose:Interventional
        Overall Status:Not yet recruiting
        Lead Sponsor:M.D. Anderson Cancer Center

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