Clinical Trials

PRIMARY OBJECTIVES: I. To test whether the response rate (complete remission, partial remission, or hematologic improvement) of patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) who receive either the combination of lenalidomide and azacitidine or the combination of vorinostat and azacitidine is improved compared to patients who receive single-agent azacitidine. SECONDARY OBJECTIVES: I. To estimate relapse-free survival, overall survival and cytogenetic response rate of patients treated on each regimen. II. To estimate the frequency and severity of toxicities of the three regimens in this patient population. III. To investigate in a preliminary manner the frequency of subgroups from pre-study cytogenetic studies and correlate these subgroups with clinical outcomes in this patient population. IV. To collect specimens for banking for use in future research studies. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7 or days 1-5 and 8-9, and lenalidomide orally (PO) once daily (QD) on days 1-21. ARM II: Patients receive azacitidine as in arm I. ARM III: Patients receive azacitidine as in arm I and vorinostat PO twice daily (BID) on days 3-9. In all arms, courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 5 years.

PRIMARY OBJECTIVES:

     I. To determine the clinical efficacy (2-year disease-free survival rate) of nilotinib and combination chemotherapy in adult patients newly diagnosed with Philadelphia chromosome positive B-cell acute lymphoblastic leukemia or blast crisis of chronic myeloid leukemia.

     SECONDARY OBJECTIVES:

     I. Determine the 2-year overall survival rate. II. Determine the complete response (CR) rates (hematological, cytogenetic, and molecular) in patients treated with this regimen.

     III. Determine the CR duration in patients treated with this regimen. IV. Assess the safety and toxicity of this regimen by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

     TERTIARY OBJECTIVES:

     I. Assess the prognostic and predictive factors for patients treated with this regimen.

     II. Assess the cerebrospinal fluid (CSF) penetration for Nilotinib (CSF Nilotinib levels) in humans.

     III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during therapy, and at relapse.

     OUTLINE:

     INDUCTION AND CONSOLIDATION SCHEDULE A (COURSES 1, 3, 5, 7): Patients receive cyclophosphamide intravenously (IV) twice daily (BID) over 2 hours on days 1-3, mesna IV continuously on days 1-3, doxorubicin hydrochloride IV push on day 4, vincristine sulfate IV on days 4 and 11, dexamethasone IV or orally (PO) on days 1-4 and 11-14, methotrexate intrathecally (IT) on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.

     INDUCTION AND CONSOLIDATION SCHEDULE B (COURSES 2, 4, 6, 8): Patients receive methotrexate IV continuously over 24 hours on day 1, cytarabine IV over 2 hours on days 2-3, leucovorin calcium IV every 6 hours on days 2-3, methotrexate IT on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.

     MAINTENANCE (COURSES 9-32): Patients receive nilotinib PO BID on days 1-28 (days 1-14 for minimal residual disease [MRD]-positive patients), vincristine sulfate IV on day 1, and prednisone PO on days 1 to 5. Patients also receive rituximab IV on day 1 of each course if CD20-positive, every sixth course if MRD-negative, or every third course if MRD-positive.

     INTENSIFICATION: Patients receive treatment as in Schedule A in courses 14 and 21 of maintenance therapy and treatment as in Schedule B in courses 15 and 22 of maintenance therapy.

     DELAYED MAINTENANCE (COURSES 33-36): Patients receive nilotinib PO BID on days 1 to 84. Treatment repeats every 84 days for up to 4 courses.

     Treatment continues in the absence of disease progression or unacceptable toxicity.

     After completion of study treatment, patients are followed up every 6-12 months for 4 years.

OBJECTIVES:

       -  To provide a mechanism for sample collection and submission for diagnostic review to determine eligibility of patients with suspected leukemia or related hematologic disorders for enrollment on ECOG leukemia clinical trials.

       -  To obtain baseline samples for correlative studies outlined in parent clinical trials.

     OUTLINE: This is a cohort, multicenter study.

     Patients submit bone marrow and/or blood samples. The samples are studied to determine patients' eligibility for ECOG leukemia treatment clinical trials. Samples may be stored for future correlative studies related to ECOG treatment clinical trials.