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

• ClinicalTrials.gov Identifier: NCT00651261
• Recruitment Status: Unknown
• First Posted: April 2, 2008
• Results First Posted: February 6, 2017
• Last Update Posted: August 18, 2021
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); Novartis Pharmaceuticals
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: April 1, 2008
• First Posted Date: April 2, 2008
• Results First Submitted Date: December 12, 2016
• Results First Posted Date: February 6, 2017
• Last Update Posted Date: August 18, 2021
• Actual Study Start Date: April 2008
• Actual Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 12, 2016)

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.

• Original Primary Outcome Measures (submitted: April 1, 2008): Overall survival

Current Secondary Outcome Measures (submitted: December 12, 2016)

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

Original Secondary Outcome Measures (submitted: April 1, 2008)

• Complete response rate in the remission induction stage of the study
• Event- free survival
• Disease-free survival (DFS)
• DFS rate one year after completing the planned continuation phase

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
• 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Leukemia

Intervention

• Drug: cytarabine
  Given IV
• Drug: daunorubicin
  Given IV
• Drug: midostaurin
  Given orally
• Other: placebo
  Given orally
• Drug: dexamethasone acetate
  ocular medication administration

Study Arms

• 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.
  Interventions:

  • Drug: cytarabine
  • Drug: daunorubicin
  • Drug: midostaurin
  • Drug: dexamethasone acetate
• 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.
  Interventions:

  • Drug: cytarabine
  • Drug: daunorubicin
  • Other: placebo
  • Drug: dexamethasone acetate

Publications *

• 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.
• Voso MT, Larson RA, Jones D, Marcucci G, Prior T, Krauter J, Heuser M, Lavorgna S, Nomdedeu J, Geyer SM, Walker A, Wei AH, Sierra J, Sanz MA, Brandwein JM, de Witte TM, Jansen JH, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Schlenk RF, Ganser A, Amadori S, Cheng Y, Chen Y, Pallaud C, Du L, Piciocchi A, Ehninger G, Byrd J, Thiede C, Dohner K, Stone RM, Dohner H, Bloomfield CD, Lo-Coco F. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial. Blood Adv. 2020 Oct 13;4(19):4945-4954. doi: 10.1182/bloodadvances.2020002904.
• Walker CJ, Kohlschmidt J, Eisfeld AK, Mrozek K, Liyanarachchi S, Song C, Nicolet D, Blachly JS, Bill M, Papaioannou D, Oakes CC, Giacopelli B, Genutis LK, Maharry SE, Orwick S, Archer KJ, Powell BL, Kolitz JE, Uy GL, Wang ES, Carroll AJ, Stone RM, Byrd JC, de la Chapelle A, Bloomfield CD. Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia. Clin Cancer Res. 2019 Nov 1;25(21):6524-6531. doi: 10.1158/1078-0432.CCR-19-0725. Epub 2019 Aug 2.
• Yin J, LaPlant B, Uy GL, Marcucci G, Blum W, Larson RA, Stone RM, Mandrekar SJ. Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614). Blood Adv. 2019 Jun 11;3(11):1714-1721. doi: 10.1182/bloodadvances.2018026112.
• Stein E, Xie J, Duchesneau E, Bhattacharyya S, Vudumula U, Ndife B, Bonifacio G, Guerin A, Li N, Joseph G. Cost Effectiveness of Midostaurin in the Treatment of Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia in the United States. Pharmacoeconomics. 2019 Feb;37(2):239-253. doi: 10.1007/s40273-018-0732-4.
• Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Dohner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Dohner H. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359. Epub 2017 Jun 23.
• Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, Cortes J, Kantarjian HM, DeAngelo DJ, Huntsman-Labed A, Dutreix C, del Corral A, Giles F. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012 Sep;26(9):2061-8. doi: 10.1038/leu.2012.115. Epub 2012 Apr 27.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: November 10, 2016): 717
• Original Enrollment (submitted: April 1, 2008): 514
• Study Completion Date: Not Provided
• Actual Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 59 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT00651261
• Other Study ID Numbers: CALGB-10603; CALGB-10603; EUDRACT-2006-006852-37; CDR0000590404 ( Registry Identifier: Phyisician Data Query )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Not Provided
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: Cancer and Leukemia Group B

Collaborators

• National Cancer Institute (NCI)
• Novartis Pharmaceuticals

Investigators

• Study Chair: Richard M. Stone, MD; Dana-Farber Cancer Institute

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: August 2021