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A Study of Midostaurin Efficacy and Safety in Newly Diagnosed Patients With FLT3-mutated AML

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ClinicalTrials.gov Identifier: NCT03280030
Recruitment Status : Recruiting
First Posted : September 12, 2017
Last Update Posted : July 15, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This study will evaluate the efficacy and safety of midostaurin in combination with daunorubicin/cytarabine induction, high dose cytarabine consolidation and midostaurin single agent continuation therapy in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Midostaurin Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase II, Randomized, Double-blind, Multi-center, Placebo-controlled Study to Evaluate the Efficacy and Safety of Twice Daily Oral Midostaurin in Combination With Daunorubicin/Cytarabine Induction, High-dose Cytarabine Consolidation, and Midostaurin Single Agent Continuation Therapy in Newly Diagnosed Patients With FLT3-mutated Acute Myeloid Leukemia (AML).
Actual Study Start Date : April 6, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 20, 2022


Arm Intervention/treatment
Experimental: Midostaurin
Patients will take study drug on day 8-21 during induction and consolidation phase; then continuously during continuation phase.
Drug: Midostaurin
Midostaurin 50 mg [two 25 mg capsules] will be administered twice per day by mouth on day 8-21 during induction and consolidation phase; then continuously during continuation phase
Other Name: PKC412

Placebo Comparator: Placebo
Patients will take placebo on day 8-21 during induction and consolidation phase; then continuously during continuation phase.
Drug: Placebo
Placebo two capsules will be administered twice per day by mouth on day 8-21 during induction and consolidation phase ; then continuously during continuation phase.




Primary Outcome Measures :
  1. Incidence of Safety Evetnts (Part 1, Japan only) [ Time Frame: Day 21 of the first Consolidation cycle ]
    Incidence and severity of Safety Events, defined as death or serious adverse event leading to treatment discontinuation that occurs on or before Day 21 of the first Consolidation cycle. This is is determined by the Independent Safety Committee to be definitely or probably related to midostaurin.

  2. Event Free Survival (Part 2 - randomized, controlled) [ Time Frame: 36 months ]
    Event Free survival defined as the time from the date of randomization until an EFS event is observed. An EFS event is defined as a failure to obtain a CR within an induction 2, relapse after CR, or death due to any cause, whichever occurs first.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 51 months ]
    Overall survival defined as the time from the date of randomization to date of death due to any cause

  2. Complete Remission [ Time Frame: 51 months ]
    Complete Remission defined as the proportion of patients with a CR according to Chelson Criteria, at various timepoints

  3. Cumulative incidence of relapse (CIR) [ Time Frame: 51 months ]
    CIR (only for patients who have achieved CR after study treatment initiation), is measured from the date of first CR to relapse or death due to AML, whichever occurs first.

  4. Metabolite CGP52421 [ Time Frame: Induction 1 Cycle 1 Day 8, Day 11, Day 15, Day 18 and Day 21, Consolidation Cycle 1 Day 8, Day 21, Cycle 3 Day 8, Day 21 Prior to first cycle of continuation cycle 1, Continuation Cycle 5, Continuation Cycle 9 and Completion Cycle 12 ]
    Evaluate the pharmacokinetic of major metabolite of midostaurin CGP52421

  5. Metabolite CGP62221 [ Time Frame: Induction 1 Cycle 1 Day 8, Day 11, Day 15, Day 18 and Day 21, Consolidation Cycle 1 Day 8, Day 21, Cycle 3 Day 8, Day 21 Prior to first cycle of continuation cycle 1, Continuation Cycle 5, Continuation Cycle 9 and Completion Cycle 12 ]
    Evaluate the pharmacokinetic of major metabolite of Midostaurin CGP62221.

  6. Quality of life (QoL) per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [ Time Frame: Screening, D21 of each cycle of Induction and Consolidation; D1 of each cycle of Continuation, at end of treatment and during the post treatment follow up every 4 months during the first year ]
    EORTC)QLQ-C30 total score and functional scales scores as determined by the score and absolute change from baseline at each scheduled assessment.

  7. Quality of life (QoL) per Patient Global Impression of Change (PGIC) [ Time Frame: D21 of each cycle of Induction and Consolidation; D1 of each cycle of Continuation, at end of treatment and during the post treatment follow up every 4 months during the first year ]
    PGIC score determined frequencies and percentages by scheduled timepoint.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of AML (≥ 20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible
  • Documented presence of an ITD and/or TKD activating mutation in the FLT3 gene, as determined by analysis in a Novartis designated laboratory An exception will be patients who are enrolled into the part 1 in Japan, who may be treated with midostaurin irrespective of AML FLT3 genotype.
  • Patients must meet the following laboratory value criteria that indicate adequate organ function at the screening visit:

    • Estimated creatinine clearance ≥ 30 ml/min
    • Total bilirubin ≤ 1.5 x ULN, except in the setting of isolated Gilbert syndrome
    • Aspartate transaminase (AST) ≤ 3.0 x ULN
    • Alanine transaminase (ALT) ≤ 3.0 x ULN
  • Suitability for intensive chemotherapy in the judgment of the investigator

Exclusion Criteria:

  • Neurologic symptoms suggestive of CNS leukemia unless CNS leukemia has been excluded by a lumbar puncture. Patients with CSF fluid positive for AML blasts are not eligible
  • Developed therapy-related AML after prior radiotherapy (RT) or chemotherapy for another cancer or disorder
  • Known hypersensitivity to midostaurin, cytarabine or daunorubicin or to any of the excipients of midostaurin/placebo, cytarabine or daunorubicin
  • Abnormal chest X-ray unless the abnormality represents a non-active, or non-clinically significant finding, such as scarring (subjects with controlled non active lung infection are eligible)
  • Known impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin
  • Cardiac or cardiac repolarization abnormality
  • Pregnant or nursing (lactating) women
  • Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 4 months after stopping medication Other protocol-defined Inclusion/Exclusion criteria may apply.

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): NCT03280030


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +81337978748

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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03280030     History of Changes
Other Study ID Numbers: CPKC412A2220
First Posted: September 12, 2017    Key Record Dates
Last Update Posted: July 15, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
midostaurin
PKC412
cytarabine
daunorubicin
acute myeloid leukemia
combination treatment
FLT3
acute myeloid leukemia (AML)
acute myelogenous leukemia (AML)
Additional relevant MeSH terms:
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Cytarabine
Daunorubicin
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Midostaurin
Staurosporine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protein Kinase Inhibitors