Phase I Study of Lenalidomide and Conventional Chemotherapy in Acute Myeloid Leukemia
Overview
- Phase
- Phase 1
- Intervention
- Lenalidomide
- Conditions
- Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 61
- Locations
- 1
- Primary Endpoint
- MTD of lenalidomide, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of lenalidomide when given together with cytarabine and idarubicin in treating patients with acute myeloid leukemia. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as cytarabine and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with cytarabine and idarubicin may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of lenalidomide in combination with conventional chemotherapy in two separate cohorts of patients with 1) relapsed or refractory acute myeloid leukemia (AML) and 2) age \>= 60 with untreated AML and recommend starting doses for phase II studies of this combination of agents. SECONDARY OBJECTIVES: I. To define the qualitative and quantitative toxicities of these combinations of agents in regard to organ specificity, time course, predictability, and reversibility. II. To document the therapeutic response of these combinations of agents in patients with poor risk AML. III. To conduct pharmacodynamic studies to investigate the potential mechanism of lenalidomide activity in this trial. OUTLINE: This is a dose-escalation study of lenalidomide. INDUCTION: COHORT I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, cytarabine intravenously (IV) continuously over 96 hours on days 5-8, and idarubicin IV over 1 hour on days 5-7. COHORT II: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 24 hours on days 5-11, and idarubicin as above. Patients with residual disease on day 18 undergo a second course of induction therapy. CONSOLIDATION: COHORT I: Patients receive lenalidomide PO QD on days 1-14, idarubicin IV over 1 hour on days 5-6, cytarabine IV continuously on days 5-7. Treatment continues for 1 course in the absence of disease progression or unacceptable toxicity. COHORT II: Patients 2 receive 4 courses of consolidation therapy comprising lenalidomide PO QD on days 1-14 and cytarabine IV every 12 hours on days 5, 7, and 9. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Cohort 1: Patients must be age \>= 18 and \< 65 with relapsed or refractory AML or high risk myelodysplastic syndrome (MDS); high risk MDS is defined as international prognosis scoring system (IPSS) score of 1.5 or higher; eligible patients will have a score of 1.5 or higher at any time from diagnosis to screening
- •Cohort 2: Patients must be age \>= 18 with previously untreated AML; favorable risk AML patients \< 60 years of age are excluded; these are defined as core binding factor (CBF) AML patients and characterized by cytogenetic or molecular evidence of CBF leukemia; untreated AML patients \< 60 years of age must be negative on screening for CBF leukemia by cytogenetic or molecular analysis (Note: Prior therapy for MDS is permitted)
- •Patients with secondary AML or therapy-related disease (transformed \[t\]-AML/MDS) are eligible
- •If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
- •Total bilirubin \< 2.0 mg/dL
- •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 2.5 times upper limit of normal
- •Creatinine \< 2.0 mg/dL AND creatinine clearance (calculated) \>= 50 mL/min
- •Left ventricular ejection fraction (LVEF) \>= 40%
- •Patients who have previously received lenalidomide, idarubicin, and/or cytarabine are eligible provided that the combination of the 3 agents has never before been administered, and that no lenalidomide has been administered for at least 6 months
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 2 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 who have taken lenalidomide within the last 6 months
- •Patients receiving any other investigational agents or patients that have received other investigational agents within 14 days of enrollment
- •Patients with active central nervous system disease or with granulocytic sarcoma as sole site of disease
- •Patients with history of medically serious allergic reactions or non-hematologic toxicities attributed to the agents in this trial such as lenalidomide or thalidomide or compounds of similar chemical or biologic composition that are not easily managed, or patients with a history of cerebellar toxicity to cytarabine
- •Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled
- •Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study
- •Pregnant women or women who are breastfeeding; additional pregnancy testing before, during, and after lenalidomide treatment is required, as well as requirements for contraception before, during, and after lenalidomide treatment
- •Patients with advanced malignant solid tumors are excluded; patients with active additional hematologic malignancies are excluded
- •Patients with a history of neurologic toxicity with cytarabine are excluded
Arms & Interventions
Treatment (lenalidomide, cytarabine, idarubicin)
INDUCTION: COHORT I: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 96 hours on days 5-8, and idarubicin IV over 1 hour on days 5-7. COHORT II: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 24 hours on days 5-11, and idarubicin as above. Patients with residual disease on day 18 undergo a second course of induction therapy. CONSOLIDATION: COHORT I: Patients receive lenalidomide PO QD on days 1-14, idarubicin IV over 1 hour on days 5-6, cytarabine IV continuously on days 5-7. Treatment continues for 1 course in the absence of disease progression or unacceptable toxicity. COHORT II: Patients 2 receive 4 courses of consolidation therapy comprising lenalidomide PO QD on days 1-14 and cytarabine IV every 12 hours on days 5, 7, and 9. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Lenalidomide
Treatment (lenalidomide, cytarabine, idarubicin)
INDUCTION: COHORT I: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 96 hours on days 5-8, and idarubicin IV over 1 hour on days 5-7. COHORT II: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 24 hours on days 5-11, and idarubicin as above. Patients with residual disease on day 18 undergo a second course of induction therapy. CONSOLIDATION: COHORT I: Patients receive lenalidomide PO QD on days 1-14, idarubicin IV over 1 hour on days 5-6, cytarabine IV continuously on days 5-7. Treatment continues for 1 course in the absence of disease progression or unacceptable toxicity. COHORT II: Patients 2 receive 4 courses of consolidation therapy comprising lenalidomide PO QD on days 1-14 and cytarabine IV every 12 hours on days 5, 7, and 9. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine
Treatment (lenalidomide, cytarabine, idarubicin)
INDUCTION: COHORT I: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 96 hours on days 5-8, and idarubicin IV over 1 hour on days 5-7. COHORT II: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 24 hours on days 5-11, and idarubicin as above. Patients with residual disease on day 18 undergo a second course of induction therapy. CONSOLIDATION: COHORT I: Patients receive lenalidomide PO QD on days 1-14, idarubicin IV over 1 hour on days 5-6, cytarabine IV continuously on days 5-7. Treatment continues for 1 course in the absence of disease progression or unacceptable toxicity. COHORT II: Patients 2 receive 4 courses of consolidation therapy comprising lenalidomide PO QD on days 1-14 and cytarabine IV every 12 hours on days 5, 7, and 9. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Idarubicin
Treatment (lenalidomide, cytarabine, idarubicin)
INDUCTION: COHORT I: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 96 hours on days 5-8, and idarubicin IV over 1 hour on days 5-7. COHORT II: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 24 hours on days 5-11, and idarubicin as above. Patients with residual disease on day 18 undergo a second course of induction therapy. CONSOLIDATION: COHORT I: Patients receive lenalidomide PO QD on days 1-14, idarubicin IV over 1 hour on days 5-6, cytarabine IV continuously on days 5-7. Treatment continues for 1 course in the absence of disease progression or unacceptable toxicity. COHORT II: Patients 2 receive 4 courses of consolidation therapy comprising lenalidomide PO QD on days 1-14 and cytarabine IV every 12 hours on days 5, 7, and 9. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacological Study
Treatment (lenalidomide, cytarabine, idarubicin)
INDUCTION: COHORT I: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 96 hours on days 5-8, and idarubicin IV over 1 hour on days 5-7. COHORT II: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over 24 hours on days 5-11, and idarubicin as above. Patients with residual disease on day 18 undergo a second course of induction therapy. CONSOLIDATION: COHORT I: Patients receive lenalidomide PO QD on days 1-14, idarubicin IV over 1 hour on days 5-6, cytarabine IV continuously on days 5-7. Treatment continues for 1 course in the absence of disease progression or unacceptable toxicity. COHORT II: Patients 2 receive 4 courses of consolidation therapy comprising lenalidomide PO QD on days 1-14 and cytarabine IV every 12 hours on days 5, 7, and 9. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Outcomes
Primary Outcomes
MTD of lenalidomide, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame: 28 days
Secondary Outcomes
- Pharmacodynamic studies, including micro-ribonucleic acid (miRNA)-181 family and target gene expression, CCAAT/enhancer binding protein (C/EBP), alpha gene (CEBPA) expression, and genes involved in erythroid differentiation(Baseline, day 5, and day 28)
- Qualitative and quantitative toxicities, graded using NCI CTCAE version 4.0(Up to 30 days post-treatment)
- Therapeutic response, assessed using International Working Group criteria(Up to 30 days post-treatment)