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

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.

• Midostaurin (Drug), also known as PKC412: Midostaurin 50 mg \[two 25 mg capsules\] were administered twice per day by mouth on day 8-21 during induction and consolidation phase; then on days 1-28 for 12 cycles in the continuation (post consolidation) phase.
• Placebo (Drug): Placebo, two capsules, were administered twice per day by mouth on day 8-21 during induction and consolidation phase; then on days 1-28 for 12 cycles in the continuation (post consolidation) phase.

Primary outcomes

• Percentage of Safety Events (Part 1, Japan Only) [up to Day 21 of the first Consolidation cycle; cycle = 28 days]: Percentage 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 was determined by the Independent Safety Committee (ISC) to be definitely or probably related to midostaurin. Percentage was calculated based on the percentage of subjects with safety event out of 3 evaluable subjects in Part 1.
• Event Free Survival (EFS) (Part 2 - Randomized, Controlled) [up to 3 years after last patient started treatment]: Event Free survival is 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 complete remission (CR) within an induction 2, relapse after CR, or death due to any cause, whichever occurs first. The objective was to evaluate the efficacy based on EFS of midostaurin versus placebo in combination with daunorubicin/cytarabine induction, with high-dose cytarabine consolidation, and with midostaurin single agent continuation therapy in newly diagnosed patients with FLT3-mutated AML.

Secondary outcomes

• 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
• Percentage of Participants With Complete Remission (CR) [up to 3 years after last patient started treatment]: Complete Remission is defined as the percentage of participants with a CR according to Chelson Criteria, at various timepoints
• Percentage of Participants With Cumulative Incidence of Relapse (CIR) [up to 3 years after last patient started treatment]: CIR (only for patients who achieved CR after study treatment initiation), is measured from the date of first CR to relapse or death due to AML, whichever occurs first.
• Pharmakinetics (PK) for Midostaurin: AUClast & AUC0-t [Induction Phase: Pre-dose and 1, 3, 6 and 12 hours post dose in Cycle 1 Day 8]: Evaluate AUClast \& AUC0-t PK parameters for midostaurin. AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x time x volume-1) AUC0-t: The area under the curve (AUC) from time zero to a measurable concentration sampling time (t) (mass x time x volume-1).
• Pharmakinetics (PK) for Midostaurin: Cmax [Induction Phase: Pre-dose and 1, 3, 6 and 12 hours post dose in Cycle 1 Day 8]: Evaluate Cmax parameter for midostaurin. Cmax: The maximum (peak) observed plasma drug concentration after the first dose administration of midostaurin (mass x volume-1).
• Metabolite CGP52421: PK Parameters AUClast, AUC0-t [Induction Phase: Cycle 1 Day 8]: Evaluate the pharmacokinetic of major metabolite of midostaurin CGP52421. AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x time x volume-1) AUC0-t: The area under the curve (AUC) from time zero to a measurable concentration sampling time (t) (mass x time x volume-1).
• Metabolite CGP52421: PK Parameter Cmax [Induction Phase: Cycle 1 Day 8]: Evaluate the pharmacokinetic of major metabolite of midostaurin CGP52421: Cmax. Cmax: The maximum (peak) observed plasma drug concentration after the first dose administration of midostaurin (mass x volume-1).
• Metabolite CGP62221: PK Parameters: AUClast, AUC0-t [Induction Phase: Cycle 1 Day 8]: Evaluate the pharmacokinetic of major metabolite of Midostaurin CGP62221 PK parameters AUClast, AUC0-t
• Metabolite CGP62221: PK Parameter: Cmax [Induction Phase: Cycle 1 Day 8]: Evaluate the pharmacokinetic of major metabolite of Midostaurin CGP62221 PK parameter Cmax. Cmax: The maximum (peak) observed plasma drug concentration after the first dose administration of midostaurin (mass x volume-1).
• Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [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]: The EORTC QLQ-C30 is a 30-item questionnaire with multi-item scales and single-item measures, including five functional scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global health status/QoL scale. Scores range from 0 to 100, with higher scores indicating higher response levels. High functional scale scores denote healthy functioning, high global QoL scores indicate high QoL, and high symptom scores reflect high symptom levels. Scoring follows the EORTC Scoring Manual, reported by absolute change from baseline. EOI = End of Induction; EOCons = End of Consolidation; EOCont = End of Continuation; EOT = End of Treatment.
• Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) [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]: The PGIC is a single self-reported item that asks about change in status of subject's overall satisfaction with medication since starting the standalone study. The specific wording of the PGIC is "Directions: Circle the one number that best describes how your overall satisfaction with your medication had changed since starting the study": "Very much improved" =1; "Much improved" =2; "Minimally improved" =3; "No change" =4; "Minimally worse" =5; "Much worse" =6; "Very much worse" =7. PGI-C questions have been widely used to assess the patient perspective of improvement in clinical trials and have shown clinical validity in a variety of indications, including depression, urinary incontinence and adult asthma and the PGIC score determined frequencies and percentages by scheduled timepoint. EOI = End of Induction; EOCons = End of Consolidation; EOCont = End of Continuation; EOT = End of Treatment.

Sex: All, ages: 18 Years to 70 Years

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

Participant flow

Outcome results

• Percentage of Safety Events (Part 1, Japan Only) (Primary), Number, Participants: Midostaurin: Part 1 (Japan Only) 5; Midostaurin: Part 2 ; Placebo: Part 2
• Event Free Survival (EFS) (Part 2 - Randomized, Controlled) (Primary), Median, Months: Midostaurin: Part 2 7.6 (3.6 to NA); Placebo: Part 2 NA (8.2 to NA)
• Overall Survival (Secondary), Median, Months: Midostaurin: Part 2 NA (16.8 to NA); Placebo: Part 2 NA (18.8 to NA)
• Percentage of Participants With Complete Remission (CR) (Secondary), Number, Percentage of participants: Midostaurin: Part 2 70.0 (50.60 to 85.27); Placebo: Part 2 78.1 (60.03 to 90.72)
• Percentage of Participants With Cumulative Incidence of Relapse (CIR) (Secondary), Count of participants, Participants: Midostaurin: Part 2 21; Placebo: Part 2 25
• Pharmakinetics (PK) for Midostaurin: AUClast & AUC0-t (Secondary), Geometric mean, ng*hr/mL: Midostaurin: Part 2 17900 +/- 53.5
• Pharmakinetics (PK) for Midostaurin: Cmax (Secondary), Geometric mean, ng/mL: Midostaurin: Part 2 2420 +/- 46.5
• Metabolite CGP52421: PK Parameters AUClast, AUC0-t (Secondary), Geometric mean, ng*hr/mL: Midostaurin: Part 2 754 +/- 116
• Metabolite CGP52421: PK Parameter Cmax (Secondary), Geometric mean, ng/mL: Midostaurin: Part 2 98.6 +/- 83.5
• Metabolite CGP62221: PK Parameters: AUClast, AUC0-t (Secondary), Geometric mean, ng*hr/mL: Midostaurin: Part 2 1430 +/- 223
• Metabolite CGP62221: PK Parameter: Cmax (Secondary), Geometric mean, ng/mL: Midostaurin: Part 2 196 +/- 159
• Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (Secondary), Mean, scores on a scale: Midostaurin: Part 2 27.8 +/- 31.03; Placebo: Part 2 0.0 +/- 16.67
• Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) (Secondary), Number, Participants: Midostaurin: Part 2 1; Placebo: Part 2 0
• All Collected Deaths (Post hoc), Count of participants, Participants: Midostaurin: Part 1 (Japan Only) 3; Midostaurin: Part 2 10; Placebo: Part 2 7; Other Participants 7

Adverse events

Time frame: Adverse events were collected from first dose of study treatment to 30 days after last dose of study medication (on-treatment), up to approx. 55 months. Deaths were collected in the post-treatment survival follow up from 31 days after last dose of study medication until the end of the study, up to approx. 36 months. These are not considered AEs

Serious adverse events by term

Other adverse events by term

86 more terms not shown.

• Study Protocol (PDF, 2020-09-10)
• Statistical Analysis Plan (PDF, 2022-12-06)

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals