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

Study Overview
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Brief Summary
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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).

Official Title
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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).

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Midostaurin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midostaurin<br>Patients will take study drug on day 8-21 during induction and consolidation phase; then continuously during continuation phase. | Drug: Midostaurin<br>* 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<br>* Other names: PKC412;|
| Placebo Comparator: Placebo<br>Patients will take placebo on day 8-21 during induction and consolidation phase; then continuously during continuation phase. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 21 of the first Consolidation cycle | 
| 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. | up to 3 years after last patient started treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival defined as the time from the date of randomization to date of death due to any cause | up to 3 years after last patient started treatment | 
| Complete Remission | Complete Remission defined as the proportion of patients with a CR according to Chelson Criteria, at various timepoints | up to 3 years after last patient started treatment | 
| 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. | up to 3 years after last patient started treatment | 
| Metabolite CGP52421 | Evaluate the pharmacokinetic of major metabolite of midostaurin 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 | 
| Metabolite CGP62221 | Evaluate the pharmacokinetic of major metabolite of Midostaurin 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 | 
| 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. | 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 | 
| Quality of life (QoL) per Patient Global Impression of Change (PGIC) | PGIC score determined frequencies and percentages by scheduled timepoint. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLT3, acute myeloid leukemia, combination treatment, acute myeloid leukemia (AML), acute myelogenous leukemia (AML), midostaurin, PKC412, cytarabine, daunorubicin