Trial record 1 of 1 for:    CALGB 10603
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Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT00651261
First received: April 1, 2008
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

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 Intervention Phase
Leukemia
Drug: cytarabine
Drug: daunorubicin
Drug: midostaurin
Other: placebo
Drug: dexamethasone acetate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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)

Resource links provided by NLM:


Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • Overall survival (OS) [ Time Frame: Duration of study (Up to 10 years) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • OS where patients who receive a stem cell transplant are censored at the time of the transplant [ Time Frame: Duration of study (Up to 10 years) ] [ Designated as safety issue: No ]
  • Complete response rate in the remission induction stage of the study [ Time Frame: Duration of study (Up to 10 years) ] [ Designated as safety issue: No ]
  • Event- free survival [ Time Frame: Duration of study (Up to 10 years) ] [ Designated as safety issue: Yes ]
  • Disease-free survival (DFS) [ Time Frame: Duration of study (Up to 10 years) ] [ Designated as safety issue: No ]
  • DFS rate one year after completing the planned continuation phase [ Time Frame: 30 months ] [ Designated as safety issue: No ]

Enrollment: 717
Study Start Date: April 2008
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   18 Years to 59 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00651261

  Show 176 Study Locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
Novartis Pharmaceuticals
Investigators
Study Chair: Richard M. Stone, MD Dana-Farber Cancer Institute
  More Information

Additional Information:
No publications provided

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT00651261     History of Changes
Other Study ID Numbers: CALGB-10603, CALGB-10603, EUDRACT-2006-006852-37, CDR0000590404
Study First Received: April 1, 2008
Last Updated: July 24, 2014
Health Authority: United States: Food and Drug Administration

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:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
4'-N-benzoylstaurosporine
Cytarabine
Daunorubicin
BB 1101
Staurosporine
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014