- To determine if the addition of midostaurin (vs placebo) to induction therapy comprising daunorubicin hydrochloride and cytarabine, consolidation therapy comprising high-dose cytarabine, and continuation therapy improves overall survival of patients with newly diagnosed acute myeloid leukemia with FLT3-internal tandem duplication (ITD) or FLT-3 tyrosine kinase domain (TKD) mutations.
- To compare the complete response rate in patients treated with these regimens.
- To compare the event-free survival (EFS) of patients treated with these regimens.
- To compare the disease-free survival (DFS) of patients treated with these regimens.
- To compare the DFS rate of these patients after 1 year of continuation therapy.
- To compare the overall survival (OS) in the two groups using an analysis in which patients who receive a stem cell transplant are censored at the time of transplant.
- To assess the toxicity of these regimens in these patients.
- To describe the interaction between treatment outcome and pretreatment characteristics such as age, performance status, white blood cell count, morphology, cytogenetics, and molecular and pharmacodynamic features.
- To assess the population pharmacokinetics (PK) of midostaurin and its two major metabolites, CGP52421 and CGP62221.
- To explore the potential association between PK exposure and FLT3 status, overall survival, EFS, and clinical response in patients treated with these regimens.
OUTLINE: This is a multicenter study. Patients are stratified according to FLT3 mutation status (internal tandem duplication [ITD] allelic ratio < 0.7 vs ITD allelic ratio ≥ 0.7 vs tandem kinase domain [TKD]).
- Remission induction therapy: Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients also receive oral midostaurin twice daily on days 8-21.
- Arm II: Patients receive cytarabine and daunorubicin hydrochloride as in arm I. Patients also receive oral placebo twice daily on days 8-21.
Patients undergo bone marrow aspiration on day 21 to assess response. If residual leukemia is present on day 21 or upon subsequent bone marrow aspiration, patients proceed to second remission induction therapy.
- Second remission induction therapy: Patients receive a second course of remission induction therapy according to their initial randomization. Treatment begins on or shortly after day 24 (i.e., at least 3 days after completing prior midostaurin or placebo therapy). Within 1 week after hematologic recovery and 60 days after initiating protocol treatment, patients undergo assessment of response. Patients with residual acute myeloid leukemia are removed from study. Patients with complete response (CR) proceed to consolidation therapy.
- Remission consolidation therapy: Beginning within 2 weeks after hematologic recovery and at least 4 weeks after initiation of the last course of induction therapy, patients with CR receive high-dose cytarabine (HiDAC) IV over 3 hours every 12 hours on days 1, 3, and 5 and oral midostaurin or placebo therapy according to the initial randomization. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
- Continuation therapy: Patients who continue in CR after four courses of HiDAC consolidation therapy receive continuation therapy with midostaurin or placebo alone according to their initial randomization. Patients who are unable to complete four courses of HiDAC consolidation therapy because of toxicity may receive continuation therapy at the discretion of the principal investigator. Beginning at least 14 days after the last dose of consolidation midostaurin or placebo and after recovery from hematologic and other significant acute toxicity, patients receive oral midostaurin or placebo twice daily on days 1-28. Treatment repeats every 28 days for up to 12 months or until relapse.
Patients may also enroll on optional pharmacokinetics study CALGB-60706.
After completion of study therapy, patients are followed periodically for up to 10 years.
- Unequivocal diagnosis of acute myeloid leukemia (AML) meeting the following criteria:
- More than 20% blasts present in the bone marrow, as defined by WHO classification
- Documented FLT3 mutation (i.e., internal tandem duplication [ITD] or point mutation), determined by analysis in a protocol-designated FLT3 screening laboratory
- No acute promyelocytic leukemia (M3)
- Patients with antecedent myelodysplasia (MDS) allowed, provided they received no prior cytotoxic (including azacytidine or decitabine) therapy for MDS
- No therapy-related AML after prior radiotherapy or chemotherapy for another disorder or cancer
- Patients with neurologic symptoms suggestive of CNS leukemia may undergo a lumbar puncture
- Patients with a positive CSF for AML blasts are not eligible
- No symptomatic congestive heart failure
- Total bilirubin < 2.5 times upper limit of normal
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use 2 methods of effective contraception during and for 12 weeks after completion of study therapy
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- No prior therapy for leukemia or myelodysplasia, except for the following:
- Emergency leukapheresis
- Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 5 days
- Cranial radiotherapy for CNS leukostasis (one dose only)
- Growth factor or cytokine support
- No concurrent hormones or other chemotherapy, except steroids given for hypersensitivity or transfusion reactions or hormones for non-disease-related conditions (e.g., insulin for diabetes)
- No concurrent apprepitant
- No concurrent enrollment on another clinical trial with investigational agents
Last updated: 04/04/2013
NCT ID: NCT00651261