Clinical trial NCT03280030: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: midostaurin
PKC412
cytarabine
daunorubicin
acute myeloid leukemia
combination treatment
FLT3
acute myeloid leukemia (AML)
acute myelogenous leukemia (AML)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-09-12
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluated 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).

Detailed description: This was a Phase II, multi-center trial consisting of two parts; Part 1: an open label, safety evaluation part in Japan only (minimum of three evaluable subjects) and Part 2: a double-blind, randomized, placebo-controlled part (60 subjects). Part 1 in Japan and Part 2 outside Japan were initiated simultaneously. Part 1 was conducted to evaluate the safety and tolerability of midostaurin in combination with daunorubicin/cytarabine induction and high-dose cytarabine consolidation in Japanese subjects and was a pre-requisite before allowing participation of Japan in Part 2. Data from Part 1 was reviewed by an Independent safety Committee (ISC) designated by the Sponsor. The ISC reviewed all available safety data in subjects from Japan up to the time of the safety review data cut-off date (6-Sep-2018). A meeting with the ISC was held on 25-Sep-2018: based on safety evaluation in three evaluable subjects, the ISC members recommended to start Part 2 in Japan.

Part 2 of the study included screening phase, treatment phase composed of up to 18 cycles of midostaurin/placebo treatment in combination with chemotherapy (daunorubicin and cytarabine) during induction and consolidation and alone during continuation and 30 days safety follow up from last dose of study treatment (daunorubicin or cytarabine or midostaurin/placebo); and follow up phase for continued remission and survival follow-up (until 36 months after Day 1 of the last subject). Subjects who provided written informed consent were screened for eligibility during the period up to 7 days immediately prior to starting chemotherapy (Day 1). The subject was randomized at Day 8 to receive either midostaurin or placebo only if FLT3 status was mutated. Treatment phase included induction, consolidation and continuation therapies.

Induction therapy: All screened subjects started induction therapy with chemotherapy from Day 1 to Day 7, while the FLT3 mutation status was being determined. Subjects who achieved CR already with induction Cycle 1 went directly to consolidation therapy without a second cycle of induction therapy. Subjects who did not achieve CR with one cycle of induction received a second induction cycle with same treatment as in Cycle 1. Subjects who did not achieve CR after induction 2 discontinued the study treatment and were followed in safety follow up and survival follow-up.

Consolidation therapy: Subjects who achieved a CR after 1 or 2 cycles of induction received consolidation therapy with 3 cycles of high-dose cytarabine for the Japan Adult Leukemia Study Group (JALSG) regimen and 4 cycles of high-dose cytarabine as tolerated for the Randomized AML Trial In FLT3+ subjects \<60 Years old (RATIFY) regimen. Subjects received midostaurin/placebo, orally twice a day, on Days 8 to 21 of each cycle. Each consolidation cycle began within two weeks following hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) but no sooner than four weeks from the beginning of the previous cycle.

Continuation therapy: After hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) following the final cycle of consolidation but no sooner than 14 days after the last dose of midostaurin/placebo during the last consolidation cycle, subjects who maintained a CR received up to 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice a day. Safety was assessed in this treatment phase for each subject until 30 days after the end of treatment (EOT) and included routine safety monitoring.

The follow-up phases included post treatment follow-up and survival follow-up. During post-treatment follow-up, all subjects continued to be assessed for relapse i.e. every 2 months during years 1 and 2, every 3 months on year 3 and 4 and then yearly and at time of relapse until relapse, withdrawal of consent, death, loss to follow up, or end of study, whichever was earlier following the end of study treatment for any reason other than persistent AML. Subjects who discontinued study treatment due to persistent AML or relapse and the post treatment follow-up phase due to relapse entered a survival follow-up period during which survival was recorded every 3 months. Survival information was obtained by clinical visits or telephone calls or other means until death, withdrawal of consent, lost to follow-up or end of study, whichever was earlier.

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

Primary outcomes:
measure: Percentage of Safety Events (Part 1, Japan Only)
timeFrame: up to Day 21 of the first Consolidation cycle; cycle = 28 days
measure: Event Free Survival (EFS) (Part 2 - Randomized, Controlled)
timeFrame: up to 3 years after last patient started treatment
Secondary outcomes:
measure: Overall Survival
timeFrame: up to 3 years after last patient started treatment
measure: Percentage of Participants With Complete Remission (CR)
timeFrame: up to 3 years after last patient started treatment
measure: Percentage of Participants With Cumulative Incidence of Relapse (CIR)
timeFrame: up to 3 years after last patient started treatment
measure: Pharmakinetics (PK) for Midostaurin: AUClast & AUC0-t
timeFrame: Induction Phase: Pre-dose and 1, 3, 6 and 12 hours post dose in Cycle 1 Day 8
measure: Pharmakinetics (PK) for Midostaurin: Cmax
timeFrame: Induction Phase: Pre-dose and 1, 3, 6 and 12 hours post dose in Cycle 1 Day 8
measure: Metabolite CGP52421: PK Parameters AUClast, AUC0-t
timeFrame: Induction Phase: Cycle 1 Day 8
measure: Metabolite CGP52421: PK Parameter Cmax
timeFrame: Induction Phase: Cycle 1 Day 8
measure: Metabolite CGP62221: PK Parameters: AUClast, AUC0-t
timeFrame: Induction Phase: Cycle 1 Day 8
measure: Metabolite CGP62221: PK Parameter: Cmax
timeFrame: Induction Phase: Cycle 1 Day 8
measure: Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
timeFrame: EOI: up to 1.84 months (after 2 cycles); EOCons: up to 5.52 months (after 4 cycles); EOCont: up to 16.56 months (after 12 cycles); EOT: up to 16.56 months maximum, depending on treatment duration; each cycle = 28 days
measure: Quality of Life (QoL) Per Patient Global Impression of Change (PGIC)
timeFrame: EOI: up to 1.84 months (after 2 cycles); EOCons: up to 5.52 months (after 4 cycles); EOCont: up to 16.56 months (after 12 cycles); EOT: up to 16.56 months maximum, depending on treatment duration; each cycle = 28 days
Other outcomes:
Locations:
city: Pokfulam
country: Hong Kong
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Toyoake city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Sapporo
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Isehara
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Nagasaki-city
country: Japan
facility: Novartis Investigative Site
state: Nagasaki
city: Okayama city
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Osaka Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Hamamatsu
country: Japan
facility: Novartis Investigative Site
state: Shizuoka
city: Shimotsuke
country: Japan
facility: Novartis Investigative Site
state: Tochigi
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinagawa ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Aomori
country: Japan
facility: Novartis Investigative Site
city: Fukuoka
country: Japan
facility: Novartis Investigative Site
city: Kochi
country: Japan
facility: Novartis Investigative Site
city: Kyoto
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Yamagata
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Putzu City
country: Taiwan
facility: Novartis Investigative Site
state: Chiayi Hsien
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: