Clinical Trials /

Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia

NCT02890329

Description:

This phase I trial studies the side effects and best dose of ipilimumab when given together with decitabine in treating patients with myelodysplastic syndrome or acute myeloid leukemia that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ipilimumab and decitabine may work in treating patients with relapsed or refractory myelodysplastic syndrome or acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia
  • Official Title: A Phase 1 Study of Ipilimumab in Combination With Decitabine in Relapsed or Refractory Myelodysplastic Syndrome/Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01326
  • SECONDARY ID: NCI-2016-01326
  • SECONDARY ID: 17-718
  • SECONDARY ID: 10026
  • SECONDARY ID: 10026
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT02890329

Conditions

  • Recurrent Acute Myeloid Leukemia
  • Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes
  • Recurrent Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory Myelodysplastic Syndrome
  • Secondary Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineArm A (decitabine, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm A (decitabine, ipilimumab)

Purpose

This phase I trial studies the side effects and best dose of ipilimumab when given together with decitabine in treating patients with myelodysplastic syndrome or acute myeloid leukemia that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ipilimumab and decitabine may work in treating patients with relapsed or refractory myelodysplastic syndrome or acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of
      combination decitabine and ipilimumab for relapsed or refractory myelodysplastic syndrome
      (MDS) or relapsed or refractory acute myeloid leukemia (AML) in patients who are post
      allogeneic hematopoietic stem cell transplant (allo-HCT).

      II. To determine the MTD or RP2D of combination decitabine and ipilimumab for relapsed or
      refractory MDS or relapsed or refractory AML in patients who are transplant naive.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. To determine the overall response rate
      (ORR) including complete remission (CR) and complete remission with incomplete count recovery
      (CRi) for AML following 2003 International Working Group (IWG) response criteria.

      III. To determine the ORR including CR, partial remission, marrow CR, hematologic improvement
      for MDS using 2006 IWG criteria.

      IV. To determine the overall survival and progression free survival at 1 year. V. To
      determine the duration of remission. VI. To capture the incidence and severity of acute
      graft-versus-host disease (GVHD) in the post allo-HCT cohort.

      VII. To capture the incidence and severity of chronic graft-versus-host disease (GVHD) in the
      post allo-HCT cohort.

      EXPLORATORY OBJECTIVES:

      I. To measure the absolute lymphocyte count (ALC) prior to treatment and during treatment.

      II. To evaluate the genome for evidence of clonal evolution among longitudinal samples (prior
      to treatment, during treatment, and at relapse if relevant) from individual patients.

      III. To evaluate the histopathologic findings of immune response using immunohistochemistry.

      IV. To determine the immune response in the AML tumor microenvironment by using flow
      cytometry and single cell mass cytometry to evaluate T cell subsets.

      OUTLINE: This is a dose-escalation study of ipilimumab.

      ARM A (PATIENTS POST ALLO-HCT):

      PRIMING PHASE: Patients receive decitabine intravenously (IV) over 60 minutes on days 1-5 out
      of 28 days.

      INDUCTION PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV
      over 90 minutes on day 1. Treatment repeats every 28 days for up to 4 cycles in the absence
      of disease progression or unacceptable toxicity.

      MAINTENANCE PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab
      IV over 90 minutes on day 1. Treatment repeats every 4 or 8 weeks for up to 4 cycles in the
      absence of disease progression or unacceptable toxicity.

      ARM B (TRANSPLANT NAIVE PATIENTS):

      PRIMING PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 out of 28 days.

      INDUCTION PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV
      over 90 minutes on day 1. Treatment repeats every 28 days for up to 4 cycles in the absence
      of disease progression or unacceptable toxicity.

      MAINTENANCE PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab
      IV over 90 minutes on day 1. Treatment repeats every 4 or 8 weeks for up to 4 cycles in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 52
      weeks (1 year).
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (decitabine, ipilimumab)ExperimentalPRIMING PHASE: Post allo-HCT patients receive decitabine IV over 60 minutes on days 1-5 out of 28 days. INDUCTION PHASE: Post allo-HCT patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Post allo-HCT patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 4 or 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Ipilimumab
Arm B (decitabine, ipilimumab)ExperimentalPRIMING PHASE: Transplant naive patients receive decitabine IV over 60 minutes on days 1-5 out of 28 days. INDUCTION PHASE: Transplant naive patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Transplant naive patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 4 or 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects with evidence of AML or myelodysplastic syndrome (MDS) that meet at least one
             of the following criteria:

               -  Relapsed AML: evidence of >= 5% blasts in the bone marrow; or reappearance of
                  blasts in the peripheral blood; or development of extramedullary disease
                  (according to 2003 IWG criteria) who relapse after:

                    -  Allogeneic hematopoietic stem cell transplant, or

                    -  After one cycle of standard cytotoxic chemotherapy or two cycles of any
                       hypomethylating agent-based therapy

               -  Refractory AML: =< 2 prior induction regimens (example: patients who receive 7+3
                  followed by 5+2 would count as one induction regimen) or a minimum of two cycles
                  of any hypomethylating agent-based therapy

               -  Treatment-naive AML: must be 75 years and older with de novo or secondary AML to
                  be considered eligible

               -  Relapsed MDS: disease recurrence after CR, partial remission (PR) or hematologic
                  improvement with bone marrow blasts >= 5% who relapse after:

                    -  Allogeneic hematopoietic stem cell transplant, or

                    -  After four cycles of any hypomethylating agent-based therapy

               -  Refractory MDS: disease progression at any time after initiation of
                  hypomethylating agent treatment or persistent bone marrow blasts >= 5% despite a
                  minimum of four cycles of hypomethylating agent therapy

               -  Untreated or previously treated therapy- related or secondary MDS

          -  Allowed prior allogeneic hematopoietic stem cell transplantation (allo-HCT) regardless
             of stem cell source; patients must be at least 3 months post allo-HCT (at time of
             treatment start); mismatched transplantations would be allowed

          -  Patients must be off systemic immunosuppressive medications > 2 weeks prior to
             treatment start; if patients are in systemic corticosteroids and must be on a dose of
             prednisone 5 mg/day or less (or equivalent), then patients must be on this reduced
             dose for > 1 week prior to treatment start; topical steroids are allowed

          -  If post allo-HCT, then patient must have baseline donor T cell chimerism of >= 20%
             (from peripheral blood); evaluation can be made within 4 weeks of treatment start

          -  No limitations on prior therapies

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Total bilirubin =< 1.5 x local institutional upper limit of normal (ULN)

               -  If elevated total bilirubin is due Gilbert's disease or disease-related hemolysis
                  then total bilirubin =< 3.0 x local institutional ULN

          -  Aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase (SGOT) =<
             3.0 x local institutional ULN

          -  Alanine aminotransferase (ALT) or serum glutamic pyruvic transaminase (SGPT) =< 3.0 x
             local institutional ULN

          -  Serum creatinine =< 2.0 x local institutional ULN

          -  Negative serum pregnancy test for women who are of child bearing potential (test must
             be repeated if performed > 72 hours from treatment start); the effects of ipilimumab
             on the developing human fetus are unknown; for this reason and because immunotherapy
             agents as well as decitabine are known to be teratogenic, women of child-bearing
             potential 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; should a woman become pregnant or suspect she is pregnant while she or
             her partner is participating in this study, she should inform her treating physician
             immediately; men treated or enrolled on this protocol must also agree to use adequate
             contraception prior to the study, for the duration of study participation, and 4
             months after completion of study drug administration

          -  Patients with known active human immunodeficiency virus (HIV) infection; patients with
             chronic HIV with a CD4 > 250, undetectable viral load by polymerase chain reaction
             (PCR), without opportunistic infection, and on a stable regimen of highly active
             anti-retroviral therapy (HAART) therapy would be eligible

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

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy within 2 weeks prior to
             treatment start or those who have not recovered from adverse events due to agents
             administered more than 2 weeks prior to treatment start

               -  Hydroxyurea is allowed for symptomatic leukocytosis if clinically necessary; a
                  total white blood cell (WBC) count < 25 x 10^9/L prior to first dose of
                  decitabine on trial is required; prior leukapheresis and/or prior or concurrent
                  treatment with hydroxyurea to achieve this level are allowed

               -  Ongoing concurrent hormonal therapy is allowed

          -  Participants with known central nervous system (CNS) involvement with leukemia or who
             are receiving intrathecal chemotherapy for active CNS leukemia

               -  Those with a history of CNS involvement that has been completely treated and
                  those who require intrathecal chemotherapy prophylaxis are eligible in the
                  expansion cohorts

          -  Prior hypomethylating agent (HMA) therapy is allowed, however this study excludes
             patients with progression or relapse that occur while receiving HMA-based therapy
             within 12 weeks prior to treatment start on study; disease progression is defined as
             either: (1) patients with prior MDS who progress to AML (defined by the presence of >=
             20% blasts in peripheral blood or bone marrow) on HMA-based therapy; OR (2) patients
             with AML with evidence of progressive disease according to European Leukemia Net [ELN]
             2017 criteria) (e.g. > 50% increase in marrow blasts over baseline or > 50% increase
             in peripheral blasts to > 25 x10^9/L (> 25,000/uL) (in absence of differentiation
             syndrome)

               -  (Note: Patients who relapse post-transplant who received HMA treatment prior to
                  transplant are eligible for study)

          -  Donor lymphocyte infusion within 8 weeks prior to treatment start if post-transplant

          -  For patients that are post-transplant, ineligible patients include those with a
             history of overall grade III or IV (severe) acute GVHD at any time even if resolved

          -  Patients with a history of prior treatment with anti-CTLA-4, anti-PD 1 antibody, or
             anti-PDL1 antibody

          -  Participants who are receiving any other investigational agents

          -  Participants with known CNS involvement with leukemia or who are receiving intrathecal
             chemotherapy that is either prophylactic or therapeutic; history of CNS involvement
             that has been completely treated (no longer receiving intrathecal chemotherapy) will
             be allowed

          -  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; any other prior or ongoing condition, in the opinion of the
             investigator, that could adversely affect the safety of the patient or impair the
             assessment of study results; as patients with AML and MDS are prone to infections, if
             patients are actively being treated with appropriate antibiotics or antifungal therapy
             with clinical evidence of infection control, then they will be considered eligible for
             study

          -  Autoimmune disease: Patients who are not eligible include those with a history of
             inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are
             excluded from this study, as are patients with a history of symptomatic disease (e.g.,
             rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus
             erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]); CNS or motor
             neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and
             myasthenia gravis, multiple sclerosis); patients with a history of autoimmune disease
             (specifically including: diabetes mellitus, vitiligo, Hashimoto's thyroiditis) who are
             asymptomatic, do not require immune suppression or steroids, and do not have
             threatened vital organ function from these conditions may be considered after
             discussion with the principal investigator (PI)

          -  No concurrent active malignancies are allowed on study for >= 2 years prior to
             treatment start with the exception of currently treated basal cell or squamous cell
             carcinoma of the skin, or carcinoma in-situ of the cervix or breast

          -  Patients with known active hepatitis B virus (HBV) infection should be excluded
             because of potential effects on immune function and/or drug interactions; however, if
             a patient has HBV history with an undetectable HBV load by polymerase chain reaction
             (PCR), no liver-related complications, and is on definitive HBV therapy, then he/she
             would be eligible for study

          -  Patients with known active hepatitis C virus (HCV) infection; patients with a history
             of HCV infection who received definitive therapy and has an undetectable viral load by
             PCR would be eligible

          -  Pregnant women are excluded from this study because ipilimumab has 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
             ipilimumab, breastfeeding should be discontinued if the mother is treated with
             ipilimumab; these potential risks may also apply to decitabine
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (recommended phase 2 dose) of ipilimumab in combination with decitabine
Time Frame:Up to 56 days
Safety Issue:
Description:Defined as the highest dose at which 1 or fewer of 6 patients experience a dose limiting toxicity graded by Common Terminology Criteria for Adverse Events version 5.0 criteria.

Secondary Outcome Measures

Measure:Clinical response to treatment
Time Frame:Up to 52 weeks
Safety Issue:
Description:Assessed by 2003 International Working Group criteria for acute myeloid leukemia and 2006 International Working Group criteria for myelodysplastic syndrome.
Measure:Anti-leukemic activity described in terms of best overall response rate
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be assessed by 2003 International Working Group response criteria for acute myeloid leukemia and 2006 International Working Group criteria for myelodysplastic syndrome. For acute myeloid leukemia, overall response rate includes complete remission + complete remission with incomplete count recovery; for myelodysplastic syndrome, overall response rate includes complete remission + marrow complete remission + partial remission + hematologic improvement.
Measure:Anti-leukemic activity described in terms of progression free survival
Time Frame:Time from registration to the earlier of progression or death due to any cause, assessed up to 52 weeks
Safety Issue:
Description:Will be assessed by 2003 International Working Group criteria for acute myeloid leukemia and 2006 International Working Group criteria for myelodysplastic syndrome. Time to event summaries will use the Kaplan-Meier method.
Measure:Anti-leukemic activity described in terms of overall survival
Time Frame:Time from registration to death due to any cause or censored at the date last known alive, assessed up to 52 weeks
Safety Issue:
Description:Will be assessed by 2003 International Working Group criteria for acute myeloid leukemia and 2006 International Working Group criteria for myelodysplastic syndrome. Time to event summaries will use the Kaplan-Meier method.
Measure:Incidence of acute graft-versus-host disease
Time Frame:Up to 100 days
Safety Issue:
Description:Will be separately evaluated in patients in the post-allogeneic hematopoietic stem cell transplant cohort, and compared to events with response to treatment. Graft-versus-host disease for the patients on the post-transplant arm will be estimated and reported with a 90% exact binomial confidence interval.
Measure:Incidence of chronic graft-versus-host disease
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be separately evaluated in patients in the post-allogeneic hematopoietic stem cell transplant cohort, and compared to events with response to treatment. Graft-versus-host disease for the patients on the post-transplant arm will be estimated and reported with a 90% exact binomial confidence interval.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 3, 2020