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

Primary Purpose

Acute Myeloid Leukemia

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Midostaurin
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring midostaurin, PKC412, cytarabine, daunorubicin, acute myeloid leukemia, combination treatment, FLT3, acute myeloid leukemia (AML), acute myelogenous leukemia (AML)

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Midostaurin

Placebo

Arm Description

Patients will take study drug on day 8-21 during induction and consolidation phase; then continuously during continuation phase.

Patients will take placebo on day 8-21 during induction and consolidation phase; then continuously during continuation phase.

Outcomes

Primary Outcome Measures

Incidence of Safety Events (Part 1, Japan only)
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.
Event Free Survival (Part 2 - randomized, controlled)
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

Overall Survival
Overall survival defined as the time from the date of randomization to date of death due to any cause
Complete Remission
Complete Remission defined as the proportion of patients with a CR according to Chelson Criteria, at various timepoints
Cumulative incidence of relapse (CIR)
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.
Metabolite CGP52421
Evaluate the pharmacokinetic of major metabolite of midostaurin CGP52421
Metabolite CGP62221
Evaluate the pharmacokinetic of major metabolite of Midostaurin CGP62221.
Quality of life (QoL) per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
EORTC)QLQ-C30 total score and functional scales scores as determined by the score and absolute change from baseline at each scheduled assessment.
Quality of life (QoL) per Patient Global Impression of Change (PGIC)
PGIC score determined frequencies and percentages by scheduled timepoint.

Full Information

First Posted
September 8, 2017
Last Updated
April 18, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT03280030
Brief Title
A Study of Midostaurin Efficacy and Safety in Newly Diagnosed Patients With FLT3-mutated AML
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).
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
April 6, 2018 (Actual)
Primary Completion Date
March 11, 2020 (Actual)
Study Completion Date
November 14, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
midostaurin, PKC412, cytarabine, daunorubicin, acute myeloid leukemia, combination treatment, FLT3, acute myeloid leukemia (AML), acute myelogenous leukemia (AML)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
75 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Midostaurin
Arm Type
Experimental
Arm Description
Patients will take study drug on day 8-21 during induction and consolidation phase; then continuously during continuation phase.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will take placebo on day 8-21 during induction and consolidation phase; then continuously during continuation phase.
Intervention Type
Drug
Intervention Name(s)
Midostaurin
Other Intervention Name(s)
PKC412
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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 Measure Information:
Title
Incidence of Safety Events (Part 1, Japan only)
Description
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.
Time Frame
Day 21 of the first Consolidation cycle
Title
Event Free Survival (Part 2 - randomized, controlled)
Description
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.
Time Frame
up to 3 years after last patient started treatment
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Overall survival defined as the time from the date of randomization to date of death due to any cause
Time Frame
up to 3 years after last patient started treatment
Title
Complete Remission
Description
Complete Remission defined as the proportion of patients with a CR according to Chelson Criteria, at various timepoints
Time Frame
up to 3 years after last patient started treatment
Title
Cumulative incidence of relapse (CIR)
Description
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.
Time Frame
up to 3 years after last patient started treatment
Title
Metabolite CGP52421
Description
Evaluate the pharmacokinetic of major metabolite of midostaurin 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
Title
Metabolite CGP62221
Description
Evaluate the pharmacokinetic of major metabolite of Midostaurin 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
Title
Quality of life (QoL) per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
Description
EORTC)QLQ-C30 total score and functional scales scores as determined by the score and absolute change from baseline at each scheduled assessment.
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
Title
Quality of life (QoL) per Patient Global Impression of Change (PGIC)
Description
PGIC score determined frequencies and percentages by scheduled timepoint.
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Hong Kong
Country
Hong Kong
Facility Name
Novartis Investigative Site
City
Nagoya-city
State/Province
Aichi
ZIP/Postal Code
466-8650
Country
Japan
Facility Name
Novartis Investigative Site
City
Toyoake city
State/Province
Aichi
ZIP/Postal Code
470 1192
Country
Japan
Facility Name
Novartis Investigative Site
City
Kashiwa
State/Province
Chiba
ZIP/Postal Code
277 8577
Country
Japan
Facility Name
Novartis Investigative Site
City
Fukuoka city
State/Province
Fukuoka
ZIP/Postal Code
812-8582
Country
Japan
Facility Name
Novartis Investigative Site
City
Fukushima city
State/Province
Fukushima
ZIP/Postal Code
960 1295
Country
Japan
Facility Name
Novartis Investigative Site
City
Sapporo
State/Province
Hokkaido
ZIP/Postal Code
064 0804
Country
Japan
Facility Name
Novartis Investigative Site
City
Isehara
State/Province
Kanagawa
ZIP/Postal Code
259-1193
Country
Japan
Facility Name
Novartis Investigative Site
City
Kochi city
State/Province
Kochi
ZIP/Postal Code
781 8555
Country
Japan
Facility Name
Novartis Investigative Site
City
Nagasaki-city
State/Province
Nagasaki
ZIP/Postal Code
852-8501
Country
Japan
Facility Name
Novartis Investigative Site
City
Okayama city
State/Province
Okayama
ZIP/Postal Code
701-1192
Country
Japan
Facility Name
Novartis Investigative Site
City
Osaka Sayama
State/Province
Osaka
ZIP/Postal Code
589 8511
Country
Japan
Facility Name
Novartis Investigative Site
City
Osaka-city
State/Province
Osaka
ZIP/Postal Code
543-8555
Country
Japan
Facility Name
Novartis Investigative Site
City
Hamamatsu
State/Province
Shizuoka
ZIP/Postal Code
432-8580
Country
Japan
Facility Name
Novartis Investigative Site
City
Shimotsuke
State/Province
Tochigi
ZIP/Postal Code
329-0498
Country
Japan
Facility Name
Novartis Investigative Site
City
Bunkyo ku
State/Province
Tokyo
ZIP/Postal Code
113-8677
Country
Japan
Facility Name
Novartis Investigative Site
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8603
Country
Japan
Facility Name
Novartis Investigative Site
City
Shinagawa ku
State/Province
Tokyo
ZIP/Postal Code
141 8625
Country
Japan
Facility Name
Novartis Investigative Site
City
Aomori
ZIP/Postal Code
030 8553
Country
Japan
Facility Name
Novartis Investigative Site
City
Fukuoka
ZIP/Postal Code
810-8563
Country
Japan
Facility Name
Novartis Investigative Site
City
Kyoto
ZIP/Postal Code
606 8507
Country
Japan
Facility Name
Novartis Investigative Site
City
Osaka
ZIP/Postal Code
534-0021
Country
Japan
Facility Name
Novartis Investigative Site
City
Yamagata
ZIP/Postal Code
990 9585
Country
Japan
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Seocho Gu
ZIP/Postal Code
06591
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
06351
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Kirov
ZIP/Postal Code
610027
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
123182
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
125284
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Samara
ZIP/Postal Code
443079
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
St Petersburg
ZIP/Postal Code
194044
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Putzu City
State/Province
Chiayi Hsien
ZIP/Postal Code
61363
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Kaohsiung City
ZIP/Postal Code
83301
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taoyuan
ZIP/Postal Code
33305
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Novartis Investigative Site
City
Hanoi
ZIP/Postal Code
100000
Country
Vietnam

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing 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

Learn more about this trial

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

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