A Phase 1 Study of Ipilimumab in Combination With Decitabine in Relapsed or Refractory Myelodysplastic Syndrome/Acute Myeloid Leukemia
Overview
- Phase
- Phase 1
- Intervention
- Decitabine
- Conditions
- Previously Treated Myelodysplastic Syndrome
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 54
- Locations
- 22
- Primary Endpoint
- Maximum Tolerated Dose (Recommended Phase 2 Dose) of Ipilimumab in Combination With Decitabine
- Status
- Active, Not Recruiting
- Last Updated
- 3 days ago
Overview
Brief Summary
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 better 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, dose level 0): PRIMING PHASE: Post allo-HCT patients receive decitabine intravenously (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 (3 mg/kg) 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 (3 mg/kg) 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, dose level 0): PRIMING 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 (3 mg/kg) 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 (3 mg/kg) 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 A (PATIENTS POST ALLO-HCT, dose level 1): PRIMING 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 (5 mg/kg) 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 (5 mg/kg) 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, dose level 1): PRIMING 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 (5 mg/kg) 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 (5 mg/kg) 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 A (PATIENTS POST ALLO-HCT, dose level 2): PRIMING 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 (10 mg/kg) 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 (10 mg/kg) 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, dose level 2): PRIMING 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 (10 mg/kg) 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 (10 mg/kg) 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).
Investigators
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
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 x 10\^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
Arms & Interventions
Arm A (decitabine, ipilimumab), post allo-HCT, Dose Level 0
PRIMING 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 (3 mg/kg) 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 (3 mg/kg) 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.
Intervention: Decitabine
Arm A (decitabine, ipilimumab), post allo-HCT, Dose Level 0
PRIMING 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 (3 mg/kg) 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 (3 mg/kg) 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.
Intervention: Ipilimumab
Arm A (decitabine, ipilimumab), post allo-HCT, Dose Level 1
PRIMING 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 (5 mg/kg) 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 (5 mg/kg) 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.
Intervention: Decitabine
Arm A (decitabine, ipilimumab), post allo-HCT, Dose Level 1
PRIMING 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 (5 mg/kg) 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 (5 mg/kg) 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.
Intervention: Ipilimumab
Arm A (decitabine, ipilimumab), post allo-HCT, Dose Level 2
PRIMING 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 (10 mg/kg) 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 (10 mg/kg) 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.
Intervention: Decitabine
Arm A (decitabine, ipilimumab), post allo-HCT, Dose Level 2
PRIMING 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 (10 mg/kg) 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 (10 mg/kg) 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.
Intervention: Ipilimumab
Arm B (decitabine, ipilimumab), transplant naive, Dose Level 0
PRIMING 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 (3 mg/kg) 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 (3 mg/kg) 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.
Intervention: Decitabine
Arm B (decitabine, ipilimumab), transplant naive, Dose Level 0
PRIMING 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 (3 mg/kg) 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 (3 mg/kg) 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.
Intervention: Ipilimumab
Arm B (decitabine, ipilimumab), transplant naive, Dose Level 1
PRIMING 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 (5 mg/kg) 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 (5 mg/kg) 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.
Intervention: Decitabine
Arm B (decitabine, ipilimumab), transplant naive, Dose Level 1
PRIMING 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 (5 mg/kg) 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 (5 mg/kg) 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.
Intervention: Ipilimumab
Arm B (decitabine, ipilimumab), transplant naive, Dose Level 2
PRIMING 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 (10 mg/kg) 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 (10 mg/kg) 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.
Intervention: Decitabine
Arm B (decitabine, ipilimumab), transplant naive, Dose Level 2
PRIMING 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 (10 mg/kg) 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 (10 mg/kg) 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.
Intervention: Ipilimumab
Outcomes
Primary Outcomes
Maximum Tolerated Dose (Recommended Phase 2 Dose) of Ipilimumab in Combination With Decitabine
Time Frame: Monitoring for DLTs occurs continuously on treatment during the first 8 weeks of combination therapy (56 days from the start of combination) during the induction phase only.
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 Outcomes
- Anti-leukemic Activity Described in Terms of Best Overall Response Rate(Up to 52 weeks)
- Anti-leukemic Activity Described in Terms of Progression Free Survival(Time from registration to the earlier of progression or death due to any cause, assessed up to 52 weeks)
- Anti-leukemic Activity Described in Terms of Overall Survival(Time from registration to death due to any cause or censored at the date last known alive, assessed up to 52 weeks)
- Incidence of Acute Graft-versus-host Disease(Up to 100 days)
- Incidence of Chronic Graft-versus-host Disease(Up to 52 weeks)