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
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

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) and myelodysplastic syndrome (MDS) 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 and MDS 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 and MDS 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. Patients are assigned to 1 of 3 arms.

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

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

      ARM C: Beginning at least 6 weeks post-stem cell transplant, patients 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 cycles in the absence of disease progression or
      unacceptable toxicity.

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

Trial Arms

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

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with evidence of relapsed or refractory AML or MDS following allogeneic stem
             cell transplantation

          -  Patients must have received preparative regimens to include either busulfan- or
             melphalan-based regimens

          -  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

        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.

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 will be estimated using the method of Kaplan and Meier, and distributions will be compared using the log-rank test.
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 will be estimated using the method of Kaplan and Meier, and distributions will be compared using the log-rank test.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

January 22, 2020