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

Acute Myeloid Leukemia Clinical Trial

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03280030
• Other study ID #: CPKC412A2220
• Status: Completed
• Phase: Phase 2
• Start date: April 6, 2018
• Est. completion date: November 14, 2022

Study information

• Verified date: April 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 75
• Est. completion date: November 14, 2022
• Est. primary completion date: March 11, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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
• 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.

Locations

Country	Name	City	State
Hong Kong	Novartis Investigative Site	Hong Kong
Japan	Novartis Investigative Site	Aomori
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Fukushima city	Fukushima
Japan	Novartis Investigative Site	Hamamatsu	Shizuoka
Japan	Novartis Investigative Site	Isehara	Kanagawa
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Kochi city	Kochi
Japan	Novartis Investigative Site	Kyoto
Japan	Novartis Investigative Site	Nagasaki-city	Nagasaki
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Japan	Novartis Investigative Site	Okayama city	Okayama
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka Sayama	Osaka
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Japan	Novartis Investigative Site	Shimotsuke	Tochigi
Japan	Novartis Investigative Site	Shinagawa ku	Tokyo
Japan	Novartis Investigative Site	Toyoake city	Aichi
Japan	Novartis Investigative Site	Yamagata
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Russian Federation	Novartis Investigative Site	Kirov
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Samara
Russian Federation	Novartis Investigative Site	St Petersburg
Taiwan	Novartis Investigative Site	Kaohsiung City
Taiwan	Novartis Investigative Site	Putzu City	Chiayi Hsien
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
Thailand	Novartis Investigative Site	Bangkok
Vietnam	Novartis Investigative Site	Hanoi

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Hong Kong,  Japan,  Korea, Republic of,  Russian Federation,  Taiwan,  Thailand,  Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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