Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
- Conditions
- Leukemia
- Interventions
- Registration Number
- NCT00651261
- Lead Sponsor
- Alliance for Clinical Trials in Oncology
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 717
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Induction and consolidation chemotherapy plus placebo daunorubicin 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. Induction and consolidation chemotherapy plus placebo placebo 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. Induction and consolidation chemotherapy plus midostaurin cytarabine 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. Induction and consolidation chemotherapy plus midostaurin daunorubicin 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. Induction and consolidation chemotherapy plus midostaurin midostaurin 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. Induction and consolidation chemotherapy plus placebo cytarabine 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. Induction and consolidation chemotherapy plus midostaurin dexamethasone acetate 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. Induction and consolidation chemotherapy plus placebo dexamethasone acetate 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.
- Primary Outcome Measures
Name Time Method Overall Survival (OS) Duration of study (Up to 10 years) 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.
- Secondary Outcome Measures
Name Time Method Overall Survival, Censoring Participants Who Receive a Stem Cell Transplant at the Time of the Transplant Duration of study (Up to 10 years) 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.
Complete Response Rate Induction therapy (up to 60 days) 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.
Disease-free Survival (DFS) Duration of study (Up to 10 years) 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.
DFS Rate One Year After Completing the Planned Continuation Phase 30 months Event- Free Survival Duration of study (Up to 10 years) 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.
Related Research Topics
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Trial Locations
- Locations (176)
UAB Comprehensive Cancer Center
🇺🇸Birmingham, Alabama, United States
Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
University of California Davis Cancer Center
🇺🇸Sacramento, California, United States
Aurora Presbyterian Hospital
🇺🇸Aurora, Colorado, United States
Boulder Community Hospital
🇺🇸Boulder, Colorado, United States
Penrose Cancer Center at Penrose Hospital
🇺🇸Colorado Springs, Colorado, United States
St. Anthony Central Hospital
🇺🇸Denver, Colorado, United States
Porter Adventist Hospital
🇺🇸Denver, Colorado, United States
Presbyterian - St. Luke's Medical Center
🇺🇸Denver, Colorado, United States
St. Joseph Hospital
🇺🇸Denver, Colorado, United States
Scroll for more (166 remaining)UAB Comprehensive Cancer Center🇺🇸Birmingham, Alabama, United States