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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03280030

Collaborator

(none)

Enrollment

Locations

Arms

55.5

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Midostaurin Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

80 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 :

Apr 6, 2018

Actual Primary Completion Date :

Mar 11, 2020

Anticipated Study Completion Date :

Nov 21, 2022

Arms and Interventions

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 Names: 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.

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 Names:

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.

Outcome Measures

Primary Outcome Measures

Incidence of Safety Events (Part 1, Japan only) [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.
Event Free Survival (Part 2 - randomized, controlled) [up to 3 years after last patient started treatment]
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 [up to 3 years after last patient started treatment]
Overall survival defined as the time from the date of randomization to date of death due to any cause
Complete Remission [up to 3 years after last patient started treatment]
Complete Remission defined as the proportion of patients with a CR according to Chelson Criteria, at various timepoints
Cumulative incidence of relapse (CIR) [up to 3 years after last patient started treatment]
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 [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
Metabolite CGP62221 [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.
Quality of life (QoL) per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [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.
Quality of life (QoL) per Patient Global Impression of Change (PGIC) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Hong Kong		Hong Kong
2	Novartis Investigative Site	Nagoya-city	Aichi	Japan	466-8650
3	Novartis Investigative Site	Toyoake city	Aichi	Japan	470 1192
4	Novartis Investigative Site	Kashiwa	Chiba	Japan	277 8577
5	Novartis Investigative Site	Matsuyama-city	Ehime	Japan	790-8524
6	Novartis Investigative Site	Fukuoka city	Fukuoka	Japan	812-8582
7	Novartis Investigative Site	Fukushima city	Fukushima	Japan	960 1295
8	Novartis Investigative Site	Gifu shi	Gifu	Japan	500 8513
9	Novartis Investigative Site	Maebashi	Gunma	Japan	371-0821
10	Novartis Investigative Site	Sapporo	Hokkaido	Japan	064 0804
11	Novartis Investigative Site	Isehara	Kanagawa	Japan	259-1193
12	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	241-8515
13	Novartis Investigative Site	Kochi city	Kochi	Japan	781 8555
14	Novartis Investigative Site	Nagasaki-city	Nagasaki	Japan	852-8501
15	Novartis Investigative Site	Okayama city	Okayama	Japan	701-1192
16	Novartis Investigative Site	Osaka Sayama	Osaka	Japan	589 8511
17	Novartis Investigative Site	Osaka-city	Osaka	Japan	543-8555
18	Novartis Investigative Site	Hamamatsu	Shizuoka	Japan	432-8580
19	Novartis Investigative Site	Shimotsuke	Tochigi	Japan	329-0498
20	Novartis Investigative Site	Bunkyo ku	Tokyo	Japan	113-8677
21	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8603
22	Novartis Investigative Site	Shinagawa ku	Tokyo	Japan	141 8625
23	Novartis Investigative Site	Aomori		Japan	030 8553
24	Novartis Investigative Site	Fukuoka		Japan	810-8563
25	Novartis Investigative Site	Kyoto		Japan	606 8507
26	Novartis Investigative Site	Osaka		Japan	534-0021
27	Novartis Investigative Site	Yamagata		Japan	990 9585
28	Novartis Investigative Site	Seoul	Seocho Gu	Korea, Republic of	06591
29	Novartis Investigative Site	Seoul		Korea, Republic of	03722
30	Novartis Investigative Site	Seoul		Korea, Republic of	06351
31	Novartis Investigative Site	Kirov		Russian Federation	610027
32	Novartis Investigative Site	Moscow		Russian Federation	123182
33	Novartis Investigative Site	Moscow		Russian Federation	125284
34	Novartis Investigative Site	Samara		Russian Federation	443079
35	Novartis Investigative Site	St Petersburg		Russian Federation	194044
36	Novartis Investigative Site	Putzu City	Chiayi Hsien	Taiwan	61363
37	Novartis Investigative Site	Kaohsiung City		Taiwan	83301
38	Novartis Investigative Site	Taipei		Taiwan	10002
39	Novartis Investigative Site	Taoyuan		Taiwan	33305
40	Novartis Investigative Site	Bangkok		Thailand	10700
41	Novartis Investigative Site	Hanoi		Vietnam