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A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)

Phase 3
18 Years
59 Years
Open (Enrolling)

Thank you

Trial Information

A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)



- 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.

Inclusion Criteria


- Unequivocal diagnosis of acute myeloid leukemia (AML) meeting the following criteria:

- More than 20% blasts present in the bone marrow, as defined by WHO

- Documented FLT3 mutation (i.e., internal tandem duplication [ITD] or point
mutation), determined by analysis in a protocol-designated FLT3 screening

- 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

- 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


- 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

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Overall survival (OS)

Outcome Time Frame:

Duration of study (Up to 10 years)

Safety Issue:


Principal Investigator

Richard M. Stone, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

April 2008

Completion Date:

Related Keywords:

  • Leukemia
  • adult acute basophilic leukemia
  • adult acute eosinophilic leukemia
  • adult acute lymphoblastic leukemia
  • adult acute megakaryoblastic leukemia (M7)
  • adult acute minimally differentiated myeloid leukemia (M0)
  • adult acute monoblastic leukemia (M5a)
  • adult acute monocytic leukemia (M5b)
  • adult acute myeloblastic leukemia with maturation (M2)
  • adult acute myeloblastic leukemia without maturation (M1)
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • adult acute myelomonocytic leukemia (M4)
  • adult erythroleukemia (M6a)
  • adult pure erythroid leukemia (M6b)
  • untreated adult acute myeloid leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid



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