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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00651261
Recruitment Status : Active, not recruiting
First Posted : April 2, 2008
Results First Posted : February 6, 2017
Last Update Posted : August 18, 2021
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Study Description
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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.

Condition or disease Intervention/treatment Phase
Leukemia Drug: cytarabine Drug: daunorubicin Drug: midostaurin Other: placebo Drug: dexamethasone acetate Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 717 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : April 2008
Actual Primary Completion Date : July 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Induction and consolidation chemotherapy plus 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.
 Drug: cytarabine
Given IV

Drug: daunorubicin
Given IV

Drug: midostaurin
Given orally

Drug: dexamethasone acetate
ocular medication administration
Active Comparator: Induction and consolidation chemotherapy plus 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.
 Drug: cytarabine
Given IV

Drug: daunorubicin
Given IV

Other: placebo
Given orally

Drug: dexamethasone acetate
ocular medication administration


Outcome Measures
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Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 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 :
  1. Event- Free Survival [ Time Frame: 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.


  2. Overall Survival, Censoring Participants Who Receive a Stem Cell Transplant at the Time of the Transplant [ Time Frame: 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.

  3. Complete Response Rate [ Time Frame: 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.

  4. Disease-free Survival (DFS) [ Time Frame: 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.

  5. DFS Rate One Year After Completing the Planned Continuation Phase [ Time Frame: 30 months ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

  1. 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.

  2. Age Requirement:

    • Age ≥ 18 and < 60 years

  3. 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.
  4. Cardiac Function: Patients with symptomatic congestive heart failure are not eligible.
  5. Initial Laboratory Value: Total bilirubin < 2.5 x ULN (Upper Limit of Normal)

  6. 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00651261


Locations
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Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Novartis Pharmaceuticals
Investigators
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Study Chair: Richard M. Stone, MD Dana-Farber Cancer Institute
More Information
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Publications of Results:
Stone RM, Dohner H, Ehninger G, et al.: CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. [Abstract] J Clin Oncol 29 (Suppl 15): A-TPS199, 2011.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT00651261    
Other Study ID Numbers: CALGB-10603
CALGB-10603
EUDRACT-2006-006852-37
CDR0000590404 ( Registry Identifier: Phyisician Data Query )
First Posted: April 2, 2008    Key Record Dates
Results First Posted: February 6, 2017
Last Update Posted: August 18, 2021
Last Verified: August 2021
Keywords provided by Alliance for Clinical Trials in Oncology:
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
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Dexamethasone
Dexamethasone acetate
Daunorubicin
Midostaurin
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
 Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Antibiotics, Antineoplastic