Acute Myeloid Leukemia
Conditions
Keywords
midostaurin, PKC412, cytarabine, daunorubicin, acute myeloid leukemia, combination treatment, FLT3, acute myeloid leukemia (AML), acute myelogenous leukemia (AML)
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.
Interventions
DRUGMidostaurin
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.
DRUGPlacebo
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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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 |
| 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. |
| 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). |
| 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 |
Countries
Hong Kong, Japan, Russia, South Korea, Taiwan, Vietnam
Participant flow
Recruitment details
Part 1 of the study enrolled 5 Japan adult subjects with newly diagnosed (ND) FLT3-mutated or non-mutated AML. Part 2 randomized 62 adult subjects with ND FLT3-mutated AML. The efficacy analysis was on the 62 randomized subjects in Part 2. The safety analysis was considered separately on 5 subjects in Part 1 & 61 out of 62 randomized subjects in Part 2, as 1 subject did not receive randomized treatment (placebo). The PK analysis was on subjects treated with midostaurin in Part 1 or Part 2.
Pre-assignment details
Subjects were enrolled in 6 countries and at 34 study centers. In Part 1, subjects started chemotherapy at day 1 and midostaurin at day 8. In Part 2, subjects started chemotherapy at day 1 and were randomized to midostaurin or placebo at day 8.
Participants by arm
| Arm | Count |
|---|---|
| Midostaurin: Part 1 (Japan Only) 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 patients. The safety evaluation period began on Day 1 of the first induction cycle (Cycle 1 Day 1) and continued until Day 21 of the first consolidation cycle. | 5 |
| Midostaurin: Part 2 Patients took study drug on day 8-21 during induction and consolidation phase, then on days 1-28 for 12 cycles in the continuation (post-consolidation) phase. | 30 |
| Placebo: Part 2 Patients took Placebo on day 8 - 21 during induction and consolidation phase, then on days 1-28 for 12 cycles in the continuation (post-consolidation) phase. | 32 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1 - Safety Evaluation | Adverse Event | 2 | 0 | 0 |
| Part 1 - Safety Evaluation | Disease progression | 1 | 0 | 0 |
| Part 1 - Safety Evaluation | Physician Decision | 2 | 0 | 0 |
| Part 2 - Efficacy | Adverse Event | 0 | 4 | 6 |
| Part 2 - Efficacy | Death | 0 | 3 | 0 |
| Part 2 - Efficacy | Physician Decision | 0 | 10 | 16 |
| Part 2 - Efficacy | Progressive disease | 0 | 7 | 5 |
| Part 2 - Efficacy | Withdrawal by Subject | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Midostaurin: Part 1 (Japan Only) | Midostaurin: Part 2 | Placebo: Part 2 |
|---|---|---|---|---|
| Age, Customized 60 - <65 years | 9 Participants | 2 Participants | 2 Participants | 5 Participants |
| Age, Customized <60 years | 53 Participants | 3 Participants | 27 Participants | 23 Participants |
| Age, Customized ≥65 years | 5 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Chinese | 13 Participants | 0 Participants | 3 Participants | 10 Participants |
| Race/Ethnicity, Customized Japanese | 29 Participants | 5 Participants | 12 Participants | 12 Participants |
| Race/Ethnicity, Customized Korean | 10 Participants | 0 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Vietnamese | 5 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 0 Participants | 9 Participants | 0 Participants |
| Sex: Female, Male Female | 35 Participants | 2 Participants | 16 Participants | 17 Participants |
| Sex: Female, Male Male | 32 Participants | 3 Participants | 14 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 5 | 3 / 30 | 1 / 31 | 2 / 4 | 7 / 27 | 6 / 30 | 7 / 7 |
| other Total, other adverse events | 5 / 5 | 30 / 30 | 31 / 31 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 2 / 5 | 12 / 30 | 10 / 31 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Event Free Survival (EFS) (Part 2 - Randomized, Controlled)
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.
Time frame: up to 3 years after last patient started treatment
Population: Full Analysis Set (FAS): The FAS comprised of all subjects to whom study drug (midostaurin/placebo) had been assigned by randomization. Therefore, all Japanese subjects treated during Part 1 were not eligible for the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Event Free Survival (EFS) (Part 2 - Randomized, Controlled) | 7.6 Months |
| Midostaurin: Part 2 | Event Free Survival (EFS) (Part 2 - Randomized, Controlled) | NA Months |
95% CI: [0.624, 2.818]
Primary
Percentage of Safety Events (Part 1, Japan Only)
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.
Time frame: up to Day 21 of the first Consolidation cycle; cycle = 28 days
Population: Patients enrolled in Part 1: 3 patients out of 5 patients in Part 1 were evaluable for safety evaluation as determined by Independent Safety Committee (ISC).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Percentage of Safety Events (Part 1, Japan Only) | Experienced at least 1 adverse event (AE) | 5 Participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Safety Events (Part 1, Japan Only) | Safety events determined by ISC related to midostaurin (n = 3, 0, 0) | 0 Participants |
Secondary
Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
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.
Time frame: 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
Population: Participants in the full analysis set (FAS) with an available assessment for the outcome measure at each timepoint. FAS: The FAS comprised of all subjects to whom study drug (midostaurin/placebo) had been assigned by randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOI: Global health status (GHS):GHS | 27.8 scores on a scale | Standard Deviation 31.03 |
| Midostaurin: Part 1 (Japan Only) | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOCons: GHS:GHS | 20.8 scores on a scale | Standard Deviation 11.49 |
| Midostaurin: Part 1 (Japan Only) | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOCont: GHS:GHS | 28.3 scores on a scale | Standard Deviation 22.52 |
| Midostaurin: Part 1 (Japan Only) | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOT:GHS:GHS | 25.5 scores on a scale | Standard Deviation 21.94 |
| Midostaurin: Part 2 | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOT:GHS:GHS | 28.8 scores on a scale | Standard Deviation 23.33 |
| Midostaurin: Part 2 | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOI: Global health status (GHS):GHS | 0.0 scores on a scale | Standard Deviation 16.67 |
| Midostaurin: Part 2 | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOCont: GHS:GHS | 27.8 scores on a scale | Standard Deviation 10.09 |
| Midostaurin: Part 2 | Change From Baseline in Quality of Life (QoL) Per European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | EOCons: GHS:GHS | 37.1 scores on a scale | Standard Deviation 24.54 |
Secondary
Metabolite CGP52421: PK Parameter Cmax
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).
Time frame: Induction Phase: Cycle 1 Day 8
Population: PAS-full: PK analysis set for full PK (PAS-full): The PAS-full included all subjects in the PAS-all, who provide an evaluable PK profile. A profile was considered evaluable if all of the following conditions are satisfied: Subject received the planned dose of midostaurin on C1D8 of induction therapy; Subject did not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction therapy; Subject provided at least one primary PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Metabolite CGP52421: PK Parameter Cmax | 98.6 ng/mL | Geometric Coefficient of Variation 83.5 |
Secondary
Metabolite CGP52421: PK Parameters AUClast, AUC0-t
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).
Time frame: Induction Phase: Cycle 1 Day 8
Population: PAS-full: PK analysis set for full PK (PAS-full): The PAS-full included all subjects in the PAS-all, who provide an evaluable PK profile. A profile was considered evaluable if all of the following conditions are satisfied: Subject received the planned dose of midostaurin on C1D8 of induction therapy; Subject did not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction therapy; Subject provided at least one primary PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Metabolite CGP52421: PK Parameters AUClast, AUC0-t | AUClast | 754 ng*hr/mL | Geometric Coefficient of Variation 116 |
| Midostaurin: Part 1 (Japan Only) | Metabolite CGP52421: PK Parameters AUClast, AUC0-t | AUC0-t | 876 ng*hr/mL | Geometric Coefficient of Variation 92.3 |
Secondary
Metabolite CGP62221: PK Parameter: Cmax
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).
Time frame: Induction Phase: Cycle 1 Day 8
Population: PAS-full: PK analysis set for full PK (PAS-full): The PAS-full included all subjects in the PAS-all, who provide an evaluable PK profile. A profile was considered evaluable if all of the following conditions are satisfied: Subject received the planned dose of midostaurin on C1D8 of induction therapy; Subject did not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction therapy; Subject provided at least one primary PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Metabolite CGP62221: PK Parameter: Cmax | 196 ng/mL | Geometric Coefficient of Variation 159 |
Secondary
Metabolite CGP62221: PK Parameters: AUClast, AUC0-t
Evaluate the pharmacokinetic of major metabolite of Midostaurin CGP62221 PK parameters AUClast, AUC0-t
Time frame: Induction Phase: Cycle 1 Day 8
Population: PAS-full: PK analysis set for full PK (PAS-full): The PAS-full included all subjects in the PAS-all, who provide an evaluable PK profile. A profile was considered evaluable if all of the following conditions are satisfied: Subject received the planned dose of midostaurin on C1D8 of induction therapy; Subject did not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction therapy; Subject provided at least one primary PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Metabolite CGP62221: PK Parameters: AUClast, AUC0-t | AUClast | 1430 ng*hr/mL | Geometric Coefficient of Variation 223 |
| Midostaurin: Part 1 (Japan Only) | Metabolite CGP62221: PK Parameters: AUClast, AUC0-t | AUC0-t | 1730 ng*hr/mL | Geometric Coefficient of Variation 182 |
Secondary
Overall Survival
Overall survival defined as the time from the date of randomization to date of death due to any cause
Time frame: up to 3 years after last patient started treatment
Population: FAS: The FAS comprised of all subjects to whom study drug (midostaurin/placebo) had been assigned by randomization. Therefore, all Japanese subjects treated during Part 1 were not eligible for the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Overall Survival | NA Months |
| Midostaurin: Part 2 | Overall Survival | NA Months |
Secondary
Percentage of Participants With Complete Remission (CR)
Complete Remission is defined as the percentage of participants with a CR according to Chelson Criteria, at various timepoints
Time frame: up to 3 years after last patient started treatment
Population: FAS: The FAS comprised of all subjects to whom study drug (midostaurin/placebo) had been assigned by randomization. Therefore, all Japanese subjects treated during Part 1 were not eligible for the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | Overall CR | 70.0 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | Morphologic CR with incomplete platelet count recovery (CRp) | 6.7 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | End of Induction cycle 1 (C1) CR | 56.7 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | End of Induction C1: Morphologic CRp | 3.3 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | End of Induction cycle 2 (C2) CR | 13.3 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | End of Induction C2: Morphologic CRp | 3.3 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | End of Consolidation CR | 36.7 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | End of Consolidation Morphologic CRp | 3.3 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | After treatment discontinuation CR | 10.0 Percentage of participants |
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Complete Remission (CR) | After treatment discontinuation Morphologic CRp | 0.0 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | End of Consolidation Morphologic CRp | 9.4 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | Overall CR | 78.1 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | End of Induction C2: Morphologic CRp | 0.0 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | Morphologic CR with incomplete platelet count recovery (CRp) | 0.0 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | After treatment discontinuation Morphologic CRp | 6.3 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | End of Induction cycle 1 (C1) CR | 65.6 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | End of Consolidation CR | 43.8 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | End of Induction C1: Morphologic CRp | 0.0 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | After treatment discontinuation CR | 3.1 Percentage of participants |
| Midostaurin: Part 2 | Percentage of Participants With Complete Remission (CR) | End of Induction cycle 2 (C2) CR | 9.4 Percentage of participants |
Secondary
Percentage of Participants With Cumulative Incidence of Relapse (CIR)
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.
Time frame: up to 3 years after last patient started treatment
Population: FAS: The FAS comprised of all subjects to whom study drug (midostaurin/placebo) had been assigned by randomization. Therefore, all Japanese subjects treated during Part 1 were not eligible for the FAS. This analysis was on FAS but only on participants who had achieved a CR.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Percentage of Participants With Cumulative Incidence of Relapse (CIR) | 21 Participants |
| Midostaurin: Part 2 | Percentage of Participants With Cumulative Incidence of Relapse (CIR) | 25 Participants |
Secondary
Pharmakinetics (PK) for Midostaurin: AUClast & AUC0-t
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).
Time frame: Induction Phase: Pre-dose and 1, 3, 6 and 12 hours post dose in Cycle 1 Day 8
Population: PK analysis set for full PK (PAS-full): The PAS-full included all subjects in the PAS-all, who provide an evaluable PK profile. A profile was considered evaluable if all of the following conditions are satisfied: Subject received the planned dose of midostaurin on C1D8 of induction therapy; Subject did not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction therapy; Subject provided at least one primary PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Pharmakinetics (PK) for Midostaurin: AUClast & AUC0-t | AUClast | 17900 ng*hr/mL | Geometric Coefficient of Variation 53.5 |
| Midostaurin: Part 1 (Japan Only) | Pharmakinetics (PK) for Midostaurin: AUClast & AUC0-t | AUC0-t | 19200 ng*hr/mL | Geometric Coefficient of Variation 49 |
Secondary
Pharmakinetics (PK) for Midostaurin: Cmax
Evaluate Cmax parameter for midostaurin. Cmax: The maximum (peak) observed plasma drug concentration after the first dose administration of midostaurin (mass x volume-1).
Time frame: Induction Phase: Pre-dose and 1, 3, 6 and 12 hours post dose in Cycle 1 Day 8
Population: PAS-full: PK analysis set for full PK (PAS-full): The PAS-full included all subjects in the PAS-all, who provide an evaluable PK profile. A profile was considered evaluable if all of the following conditions are satisfied: Subject received the planned dose of midostaurin on C1D8 of induction therapy; Subject did not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction therapy; Subject provided at least one primary PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Pharmakinetics (PK) for Midostaurin: Cmax | 2420 ng/mL | Geometric Coefficient of Variation 46.5 |
Secondary
Quality of Life (QoL) Per Patient Global Impression of Change (PGIC)
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.
Time frame: 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
Population: Participants in the full analysis set (FAS) with an available assessment for the outcome measure at each timepoint. FAS: The FAS comprised of all subjects to whom study drug (midostaurin/placebo) had been assigned by randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Very much improved | 1 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: Very much improved | 3 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Very much improved | 1 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: Much improved | 0 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Minimally improved | 3 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: Minimally improved | 1 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Much improved | 2 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: No change | 1 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Much improved | 2 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Very much improved | 5 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Minimally improved | 2 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Much improved | 4 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: No change | 1 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Minimally improved | 6 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: No change | 1 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: No change | 3 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Minimally worse | 0 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Minimally worse | 0 Participants |
| Midostaurin: Part 1 (Japan Only) | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Minimally worse | 0 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Minimally worse | 2 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Very much improved | 0 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Much improved | 1 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Minimally improved | 0 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: Minimally worse | 1 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Very much improved | 1 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Much improved | 3 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Minimally improved | 4 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: No change | 2 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCons: Minimally worse | 1 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: Very much improved | 2 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: Much improved | 4 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: Minimally improved | 0 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOCont: No change | 0 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Very much improved | 3 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Much improved | 8 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: Minimally improved | 4 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOT: No change | 3 Participants |
| Midostaurin: Part 2 | Quality of Life (QoL) Per Patient Global Impression of Change (PGIC) | EOI: No change | 1 Participants |
Post Hoc
All Collected Deaths
Pre-treatment deaths were collected from screening visit up to the first day of treatment, for a maximum duration of 21 days. Participants who died during the screening period are considered as screen failures. On-treatment deaths were collected from start of treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of approx. 55 months. Post-treatment survival follow-up deaths were collected after the on-treatment period up to approx. 36 months. Participants who did not die during the on-treatment period and had not stopped study participation at the time of data cut-off (when study was terminated) were censored.
Time frame: Start of study treatment up to 30 days post-treatment for approx. 1 year, prior to study treatment (before randomization) up to LPLV, approx. 55 months
Population: Clinical Database Population: all enrolled participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Midostaurin: Part 1 (Japan Only) | All Collected Deaths | Deaths - Not randomized to any treatment but received chemotherapy | 0 Participants |
| Midostaurin: Part 1 (Japan Only) | All Collected Deaths | Deaths on-treatment | 1 Participants |
| Midostaurin: Part 1 (Japan Only) | All Collected Deaths | Deaths - Randomized to placebo but did not receive drug | 0 Participants |
| Midostaurin: Part 1 (Japan Only) | All Collected Deaths | Post-treatment survival follow-up deaths | 2 Participants |
| Midostaurin: Part 1 (Japan Only) | All Collected Deaths | Total Deaths in study | 3 Participants |
| Midostaurin: Part 2 | All Collected Deaths | Post-treatment survival follow-up deaths | 7 Participants |
| Midostaurin: Part 2 | All Collected Deaths | Deaths - Not randomized to any treatment but received chemotherapy | 0 Participants |
| Midostaurin: Part 2 | All Collected Deaths | Deaths - Randomized to placebo but did not receive drug | 0 Participants |
| Midostaurin: Part 2 | All Collected Deaths | Deaths on-treatment | 3 Participants |
| Midostaurin: Part 2 | All Collected Deaths | Total Deaths in study | 10 Participants |
| Placebo: Part 2 | All Collected Deaths | Post-treatment survival follow-up deaths | 6 Participants |
| Placebo: Part 2 | All Collected Deaths | Total Deaths in study | 7 Participants |
| Placebo: Part 2 | All Collected Deaths | Deaths on-treatment | 1 Participants |
| Placebo: Part 2 | All Collected Deaths | Deaths - Not randomized to any treatment but received chemotherapy | 0 Participants |
| Placebo: Part 2 | All Collected Deaths | Deaths - Randomized to placebo but did not receive drug | 0 Participants |
| Other Participants | All Collected Deaths | Deaths - Not randomized to any treatment but received chemotherapy | 6 Participants |
| Other Participants | All Collected Deaths | Deaths on-treatment | 0 Participants |
| Other Participants | All Collected Deaths | Total Deaths in study | 7 Participants |
| Other Participants | All Collected Deaths | Post-treatment survival follow-up deaths | 0 Participants |
| Other Participants | All Collected Deaths | Deaths - Randomized to placebo but did not receive drug | 1 Participants |