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Ipilimumab in Treating Patients With Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01757639
First received: December 21, 2012
Last updated: November 21, 2014
Last verified: November 2014
  Purpose

This phase I trial studies the side effects and best dose of ipilimumab in treating patients with high-risk myelodysplastic syndrome or acute myeloid leukemia that has come back or no longer responds to treatment. Monoclonal antibodies, such as ipilimumab, may interfere with the ability of cancer cells to grow and spread.


Condition Intervention Phase
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1
Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL
Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA
Alkylating Agent-Related Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Previously Treated Myelodysplastic Syndrome
Recurrent Adult Acute Myeloid Leukemia
Secondary Myelodysplastic Syndrome
Biological: Ipilimumab
Other: Laboratory Biomarker Analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Ipilimumab in Relapsed and Refractory High Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia With Minimal Residual Disease

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of DLT of ipilimumab by grading and tabulation using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
  • Changes in percentages of T-regs [ Time Frame: Baseline to up to 18 months ] [ Designated as safety issue: No ]
    Changes in T-regs percentages at designated time points will be correlated with clinical responses and toxicity after ipilimumab. The response will be modeled as the vector for each individual from multiple measures of T-regs percentages as a function of time and group (MDS vs AML). T-regs percentages will be transformed onto the log-scale, and t tests will be used to compare groups at specific time points. Regression models that use generalized estimating equations will be implemented when all time points are considered to account for within-subject correlation of repeated measures.


Secondary Outcome Measures:
  • Efficacy as defined by the International working group 2006 criteria for CR, PR, HI [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    The agreement between immunologic and clinical response will be evaluated with McNemar's test, separately by cohort. Rates of CR, PR, and HI will be summarized separately by cohort and reported with an exact 95% confidence interval.

  • Progression free survival (PFS) [ Time Frame: From start of study to progression or death, assessed up to 4 years ] [ Designated as safety issue: No ]
    Median PFS will also be reported with a 95% confidence interval. As an exploratory analysis, survival endpoints will be descriptively compared with a log-rank test between patients who do and do not have an immunologic response, separately by cohort.

  • Overall survival (OS) [ Time Frame: From start of study to death, assessed up to 4 years ] [ Designated as safety issue: No ]
    Median OS will also be reported with a 95% confidence interval. As an exploratory analysis, survival endpoints will be descriptively compared with a log-rank test between patients who do and do not have an immunologic response, separately by cohort.

  • Rate of prior use of demethylating agents [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Will be descriptively compared between patients who have a clinical response and by toxicity with Fisher's exact tests.

  • Rate of pre-treatment CR [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Will be descriptively compared between patients who have a clinical response and by toxicity with Fisher's exact tests.

  • Lymphocyte counts [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Will be summarized and compared between response and toxicity groups with either t tests or Wilcoxon rank sum tests.

  • T cell receptor diversity [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Will be summarized and compared between response and toxicity groups with either t tests or Wilcoxon rank sum tests.


Estimated Enrollment: 54
Study Start Date: December 2012
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (ipilimumab)

INDUCTION: Patients receive ipilimumab IV on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Beginning 12 weeks after last dose of induction ipilimumab, patients receive ipilimumab IV on day 1. Treatment repeats every 12 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Biological: Ipilimumab
Given IV
Other Names:
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Evaluate the safety and toxicity associated with the administration of ipilimumab in terms of dose limiting toxicities (DLT), and maximally-tolerated dose (MTD) in a cohort of patients with high risk myelodysplastic syndrome who failed hypomethylating therapy, and patients with acute myeloid leukemia (AML) who underwent induction therapy but are not planned for further intensive chemotherapy. (Dose-escalation) II. Determine the optimal dose of ipilimumab for the dose-expansion phase of the trial. (Dose-escalation) III. Better define immunologic profiles associated with ipilimumab use in terms of regulatory T-cells (T-regs) dynamic changes in 2 separate cohorts of myelodysplastic syndrome (MDS) and AML patients at the optimal dose level. (Dose-expansion) IV. Obtain preliminary efficacy data of ipilimumab in terms of complete response (CR), partial response (PR), and hematological improvement (HI) in both cohorts. (Dose-expansion)

SECONDARY OBJECTIVES:

I. Define immunologic profiles associated with ipilimumab use in terms of T-regs dynamic changes at different dose levels. (Dose-escalation) II. Define toxicity profiles of ipilimumab at the optimal dose in both patient cohorts. (Dose-expansion) III. Obtain preliminary data on potential correlations between noted ipilimumab-induced immunologic changes and observed toxicity and clinical responses. (Dose-expansion)

OUTLINE: This is a dose-escalation study.

INDUCTION: Patients receive ipilimumab intravenously (IV) on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Beginning 12 weeks after last dose of induction ipilimumab, patients receive ipilimumab IV on day 1. Treatment repeats every 12 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at least monthly for 6 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be able to understand and voluntarily sign an informed consent form
  • Able to adhere to the study visit schedule and other protocol requirements
  • Life expectancy of greater than 6 months
  • Must have one of the following diagnoses:

    • Pathologically confirmed chronic myelomonocytic (CMML) or myelodysplastic syndromes (MDS) with high risk features at the time of referral for trial as defined by:

      • Intermediate (INT)-2 or high International Prognostic Scoring System (IPSS) score
      • Secondary MDS (defined as MDS developing in a patient with an antecedent hematologic disorder or any patient with prior chemotherapy or radiation exposure)
      • INT-1 MDS with excess blasts (>= 5% blasts in bone marrow [BM]) or red blood cell (RBC) transfusion-dependency
      • MDS progressing to oligoblastic acute myeloid leukemia (AML) with 21-30% BM blasts
      • CMML with >= 5% marrow blasts, or RBC or platelet transfusion-dependency, abnormal karyotype, or proliferative features (white blood cell count >=13,000/µL, splenomegaly on physical examination, or extramedullary disease)
      • All patients are required to have failed to respond or relapsed after an initial response to hypomethylating agents 5-azacitidine or decitabine or have refused to receive hypomethylating therapy; failure to respond is defined as failing to achieve a CR, PR or HI after at least 4 cycles of hypomethylating therapy; these patients could have received other therapies or not, but must have received hypomethylating therapy or have refused to receive hypomethylating therapy
    • Pathologically confirmed AML patients who have received one or two courses of induction chemotherapy or hypomethylating agent therapy AND no plans for further chemotherapy therapy, but remain with residual disease of < 5% blasts in BM, by morphology, cytogenetics, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR) or flow cytometry
  • Patients must not have received any other treatment for their disease, including hematopoietic growth factors, within three weeks of beginning the trial, and should have recovered from all toxicities of prior therapy (to grade 0 or 1)
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry ECOG, or Karnofsky >= 60%
  • Calculated creatinine clearance by Modification of Diet in Renal Disease (MDRD) (CrCL) > 50 ml/min/1.73 squared meter
  • Total bilirubin =< 2.0 mg/dL unless due to Gilbert's syndrome, hemolysis, or ineffective hematopoiesis
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal (ULN)
  • Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to start of ipilimumab
  • Patients must have no clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia
  • Patients must have no serious or uncontrolled medical conditions

Exclusion Criteria:

  • Any serious medical condition, uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, laboratory abnormality, or psychiatric illness/social situations that would limit compliance with study requirements or prevent the subject from signing the informed consent form
  • Pregnant or breast feeding females (lactating females must agree not to breast feed while taking ipilimumab)
  • Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
  • Use of any other experimental drug or therapy within 21 days of baseline
  • Known hypersensitivity to ipilimumab or history of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab
  • Prior use of ipilimumab, other cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blocking therapies, anti-programmed cell death 1 (PD 1) antibody, cluster of differentiation (CD) 137 agonist or other immune activating therapy such as anti-CD 40 antibody within the last 3 months of enrollment in the study; if any of these of these agents were used more than 3 months earlier to enrollment in study, the patient should have recovered from all toxicity and at least 3 months had passed since last use to allow for clearance and observation of any other side effects from the previous therapy
  • Concurrent use of other anti-cancer agents or treatments, including other investigational agents
  • Autoimmune disease: patients 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]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and Myasthenia Gravis, multiple sclerosis)
  • Patients with known immune impairment who may be unable to respond to anti-CTLA-4 antibody
  • Patients with known other cancers, including brain metastases
  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients with chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C infections should be excluded because of potential effects on immune function and/ or possible drug interactions
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ipilimumab
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01757639

Locations
United States, Connecticut
Yale-New Haven Hospital North Haven Medical Center Recruiting
North Haven, Connecticut, United States, 06473
Contact: Steven D. Gore    203-737-7103    steven.gore@yale.edu   
Principal Investigator: Steven D. Gore         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: B. D. Smith    410-614-5068    bdsmith@jhmi.edu   
Principal Investigator: B. D. Smith         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Mark G. Frattini    212-851-4872    mgf2122@columbia.edu   
Principal Investigator: Mark G. Frattini         
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Matthew C. Foster    919-843-2447    matthew_foster@med.unc.edu   
Principal Investigator: Matthew C. Foster         
Duke Cancer Institute Recruiting
Durham, North Carolina, United States, 27710
Contact: David A. Rizzieri    919-668-1040    david.rizzieri@dm.duke.edu   
Principal Investigator: David A. Rizzieri         
United States, Texas
Texas Oncology at Baylor Irving Cancer Center Recruiting
Irving, Texas, United States, 75061
Contact: Moshe Y. Levy    800-422-9567    mylevy@gmail.com   
Principal Investigator: Moshe Y. Levy         
Sponsors and Collaborators
Investigators
Principal Investigator: B. Smith Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01757639     History of Changes
Other Study ID Numbers: NCI-2012-02990, NCI-2012-02990, NA_00076038, CDR0000744584, J1276, 9214, UM1CA186691, P30CA006973, U01CA070095
Study First Received: December 21, 2012
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Leukemia
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Promyelocytic, Acute
Myelodysplastic Syndromes
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions

ClinicalTrials.gov processed this record on November 23, 2014