Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to compare the effects, good and/or bad, of a standard chemotherapy regimen for AML that includes the drugs daunorubicin and cytarabine combined with or without midostaurin (also known as PKC412), to find out which is better. This research is being done because it is unknown whether the addition of midostaurin to chemotherapy treatment is better than chemotherapy treatment alone. Midostaurin has been tested in over 400 patients and is being studied in a number of illnesses, including AML, colon cancer, and lung cancer. Midostaurin blocks an enzyme, produced by a gene known as FLT3, that may have a role in the survival and growth of AML cells. Not all leukemia cells will have the abnormal FLT3 gene. This study will focus only on patients with leukemia cells with the abnormal FLT3 gene.

Detailed Description
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In this study, patients will receive either the experimental agent (midostaurin) or placebo combined with chemotherapy treatment. 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]). There are three parts to the study treatment: remission induction therapy, remission consolidation therapy and continuation therapy. Remission Induction Therapy: Cytarabine 200 mg/m2/day by continuous intravenous infusion on days 1-7 Daunorubicin 60 mg/m2/day by intravenous push or short infusion on days 1-3 Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) twice a day by mouth on days 8-21 A bone marrow aspiration will be performed in all patients on Day 21 to determine the need for a second induction cycle. Remission Consolidation (Four Remission Consolidation Cycles): High dose cytarabine 3000 mg/m2 will be given by intravenous infusion over 3 hours every 12 hours on days 1, 3 and 5. Serial neurologic evaluation will be performed before and following the infusion of high-dose cytarabine. Dexamethasone 0.1% or other corticosteroid ophthalmic solution 2 drops to each eye once daily to begin 6-12 hours prior to the initiation of the cytarabine infusion and to continue for at least 24 hours after the last cytarabine dose. Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) twice a day by mouth on days 8-21 Midostaurin/Placebo Continuation Therapy: Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) by mouth twice a day for 28 days. Each cycle will be 28 days in length. Continuation therapy with midostaurin/placebo will continue until relapse or for 12 cycles maximum. The primary and secondary objectives of this study are: Primary objective: To determine if the addition of midostaurin to daunorubicin/cytarabine induction, high-dose cytarabine consolidation, and continuation therapy improves overall survival (OS) in both the mutant FLT3-ITD and FLT3-TKD AML patients Secondary objectives: 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 compare the complete response (CR) rate between the two treatment groups To compare the event-free survival (EFS) between the two treatment groups To compare the disease free survival (DFS) of the two treatment groups To compare the disease free survival rate one year after completion of the continuation phase of the two groups To assess the toxicity of the experimental combination To describe the interaction between treatment outcome and pretreatment characteristics such as age, performance status, white blood cell (WBC) count, morphology, cytogenetics, and molecular and pharmacodynamic features To assess the population pharmacokinetics (popPK) of midostaurin and its two major metabolites (CGP52421 and CGP62221). The potential association(s) between PK exposure and FLT3 status, OS, EFS and clinical response will be explored There is a pharmacokinetic sub-study (CALGB 60706) within CALGB 10603. This embedded companion study must be offered to all patients enrolled on CALGB 10603, although patients may opt not to participate in CALGB 60706. After study entry, patients are followed periodically for up to 10 years.

Official Title
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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)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: daunorubicin
* Drug: midostaurin
* Other: placebo
* Drug: dexamethasone acetate


Participation Criteria
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Eligibility Criteria
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Documentation of Disease: Unequivocal diagnosis of AML ( > 20% blasts in the bone marrow based on the WHO classification), excluding M3 (acute promyelocytic leukemia). Patients with neurologic symptoms suggestive of CNS leukemia are recommended to have a lumbar puncture. Patients whose CSF is positive for AML blasts are not eligible. Documented FLT3 mutation (ITD or point mutation), determined by analysis in a protocol- designated FLT3 screening laboratory. Age Requirement: Age ≥ 18 and < 60 years Prior Therapy: No prior chemotherapy for leukemia or myelodysplasia with the following exceptions: emergency leukapheresis emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 5 days cranial RT for CNS leukostasis (one dose only) growth factor/cytokine support AML patients with a history of antecedent myelodysplasia (MDS) remain eligible for treatment on this trial, but must not have had prior cytotoxic therapy (e.g., azacitidine or decitabine) Patients who have developed therapy related AML after prior RT or chemotherapy for another cancer or disorder are not eligible. Cardiac Function: Patients with symptomatic congestive heart failure are not eligible. Initial Laboratory Value: Total bilirubin < 2.5 x ULN (Upper Limit of Normal) Pregnancy and Nursing Status: Non-pregnant and non-nursing due to the unknown teratogenic potential of midostaurin in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential must have a negative serum or urine pregnancy test within a sensitivity of at least 50 mIU/mL within 16 days prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or commit to TWO acceptable methods of birth control: one highly effective method (eg, IUD, hormonal (non-oral contraceptive), tubal ligation, or partner's vasectomy) and one additional effective method (e.g., latex condom, diaphragm or cervical cap) The two acceptable methods of birth control must be used AT THE SAME TIME, before beginning midostaurin/placebo therapy and continuing for 12 weeks after completion of all therapy. Note that oral contraceptives are not considered a high effective method because of the possibility of a drug interaction with midostaurin. Women of childbearing potential is defined as a sexually active mature woman who has not undergone a hysterectomy or who has not had menses at any time in the preceding 24 consecutive months. Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking midostaurin/placebo and for 12 weeks after therapy is stopped, even if they have undergone a successful vasectomy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction and consolidation chemotherapy plus midostaurin<br>Patients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and the experimental drug midostaurin. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with the experimental drug midostaurin. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with midostaurin for twelve (12) months. | Drug: cytarabine<br>* Given IV<br>Drug: daunorubicin<br>* Given IV<br>Drug: midostaurin<br>* Given orally<br>Drug: dexamethasone acetate<br>* ocular medication administration<br>|
| Active Comparator: Induction and consolidation chemotherapy plus placebo<br>Patients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and placebo. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with placebo. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with placebo for twelve (12) months. | Drug: cytarabine<br>* Given IV<br>Drug: daunorubicin<br>* Given IV<br>Other: placebo<br>* Given orally<br>Drug: dexamethasone acetate<br>* ocular medication administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) was defined as the time interval from randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method. | Duration of study (Up to 10 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event- Free Survival | Event free survival (EFS) was defined as the time from randomization until the earliest qualifying event, including: failure to obtain a CR on or before 60 days of initiation of protocol therapy; relapse; or death from any cause. Patients alive and event free at the time of analysis were censored on the date of last clinical assessment. The median EFS with 95% CI was estimated using the Kaplan-Meier method. Due to a higher than expected transplant rate, EFS was promoted to be a key secondary endpoint. | Duration of study (Up to 10 years) | 
| Overall Survival, Censoring Participants Who Receive a Stem Cell Transplant at the Time of the Transplant | Overall survival (OS) was defined as the time interval from randomization to death from any cause. Any participants who received a stem cell transplant were censored at the time of transplant. The median OS with 95% CI was estimated using the Kaplan-Meier method. | Duration of study (Up to 10 years) | 
| Complete Response Rate | Percentage of participants who achieved a complete response (CR). A CR was defined as normalization of blood counts and a marrow showing less than 5% blasts occurring on or before day 60. | Induction therapy (up to 60 days) | 
| Disease-free Survival (DFS) | Disease free survival (DFS) is defined as the time from documentation of first CR at any time to the first of relapse or death from any cause in participants who achieved a CR. | Duration of study (Up to 10 years) | 
| DFS Rate One Year After Completing the Planned Continuation Phase |  | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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