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

• ClinicalTrials.gov Identifier: NCT02890329
• Recruitment Status: Active, not recruiting
• First Posted: September 7, 2016
• Last Update Posted: March 21, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Previously Treated Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia, Myelodysplasia-Related; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome	Drug: Decitabine; Biological: Ipilimumab	Phase 1

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of Ipilimumab in Combination With Decitabine in Relapsed or Refractory Myelodysplastic Syndrome/Acute Myeloid Leukemia
• Actual Study Start Date: September 5, 2017
• Estimated Primary Completion Date: July 1, 2024
• Estimated Study Completion Date: July 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A (decitabine, ipilimumab); 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 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.	Drug: Decitabine; Given IV; Other Names: 5-Aza-2'-deoxycytidine; Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; Ipilimumab Biosimilar CS1002; MDX-010; MDX-CTLA4; Yervoy
Experimental: Arm B (decitabine, ipilimumab); 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 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.	Drug: Decitabine; Given IV; Other Names: 5-Aza-2'-deoxycytidine; Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; Ipilimumab Biosimilar CS1002; MDX-010; MDX-CTLA4; Yervoy

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose (recommended phase 2 dose) of ipilimumab in combination with decitabine [ Time Frame: Up to 56 days ]
   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 :

1. Clinical response to treatment [ Time Frame: Up to 52 weeks ]
   Assessed by 2003 International Working Group criteria for acute myeloid leukemia and 2006 International Working Group criteria for myelodysplastic syndrome.
2. Anti-leukemic activity described in terms of best overall response rate [ Time Frame: Up to 52 weeks ]
   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.
3. 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 ]
   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.
4. 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 ]
   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.
5. Incidence of acute graft-versus-host disease [ Time Frame: Up to 100 days ]
   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.
6. Incidence of chronic graft-versus-host disease [ Time Frame: Up to 52 weeks ]
   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.

Other Outcome Measures:

1. Ability of absolute lymphocyte count to predict response [ Time Frame: Up to cycle 3 day 1 ]
   Absolute lymphocyte count levels will be divided into: low (< 1000 cells/ul) and normal/high (greater than or equal to 1000 cells/ul). The response and overall survival of patients with low absolute lymphocyte count versus normal/high absolute lymphocyte count will be compared using Kaplan-Meier estimates and the differences will be assessed using log-rank test.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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 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
• 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

Contacts and Locations

Locations

United States, California

City of Hope Comprehensive Cancer Center

Duarte, California, United States, 91010

UC San Diego Moores Cancer Center

La Jolla, California, United States, 92093

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States, 95817

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33612

United States, Georgia

Northside Hospital

Atlanta, Georgia, United States, 30342

United States, Massachusetts

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States, 02114

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Ohio

Case Western Reserve University

Cleveland, Ohio, United States, 44106

United States, Virginia

University of Virginia Cancer Center

Charlottesville, Virginia, United States, 22908

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jacqueline S Garcia; Dana-Farber - Harvard Cancer Center LAO

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02890329
• Other Study ID Numbers: NCI-2016-01326; NCI-2016-01326 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 17-718; 10026 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO ); 10026 ( Other Identifier: CTEP ); UM1CA186709 ( U.S. NIH Grant/Contract )
• First Posted: September 7, 2016
• Last Update Posted: March 21, 2024
• Last Verified: March 2024

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Neoplasm Metastasis; Myelodysplastic Syndromes; Syndrome; Recurrence; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Disease Attributes; Bone Marrow Diseases; Precancerous Conditions; Neoplastic Processes; Ipilimumab; Decitabine; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Enzyme Inhibitors