CPKC412A2104 core had a 2 stage design. In stage 1, eight participants were treated. If at least one participant showed a clinical response, four more participants were recruited to stage 2. The trial was to be stopped if no participants showed a response in stage 1. POC was achieved if at least 2 participants out of 12 responded. In PKC412A2104E1, participants with AML or high risk MDS with wild-type or mutant FTL3 who had not previously received a FLT3 inhibitor were randomized to receive continuous twice daily oral doses of either 50 or 100 mg midostaurin in 1 28-day cycle regimen. Participants were to be treated until disease progression or the occurrence of unacceptable treatment-related toxicity. PKC412A2104 E2 contained 2 dosing regimens: 1) intra-participant midostaurin dose escalation and 2) midostaurin with itraconazole in participants with AML and high risk MDS irrespective of FLT3 status. Eligible participants were alternately assigned to the regimens. At the Investigator's discretion, intra-participant dose escalation was allowed for any previously enrolled CPKC412A2104E1 participant receiving midostaurin at the time of the approval of amendment 4. Participants were treated until the time of disease progression.
Name: Itraconazole
Description: Itraconazole was commercially available.Type: DrugFLT3 mutated PKC+Itraconazole (E2) FLT3 wild type PKC+Itraconazole (E2)
Name: PKC412
Description: PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.Type: DrugPKC412 (Core) FLT3 mutated PKC412 100 mg/day (E1) FLT3 mutated PKC412 200 mg/day (E1) FLT3 wild type PKC412 100 mg/day (E1) FLT3 wild type PKC412 200 mg/day (E1) FLT3 mutated PKC412 dose escalation FLT3 mutated PKC+Itraconazole (E2) FLT3 wild type PKC412 dose escalation (E2) FLT3 wild type PKC+Itraconazole (E2)
Description: Best clinical response was defined as complete response (CR) or partial response (PR), according to NCI definitions for AML and the guidelines for defining responses in MDS.
Measure: Number of Participants With Best Clinical Response (Core) Time: from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003Description: Overall clinical response was defined as CR, PR, minor response (MR) or blast response (BR). CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.
Measure: Number of Participants With Overall Clinical Response (E1) Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004Description: Blood samples were collected for pharmacokinetic (PK) analysis.
Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for PKC412 Plasma in the PKC + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for pharmacokinetic (PK) analysis.
Measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) Time: Cycle 1: days 21 and 22Description: Blood samples were collected for pharmacokinetic (PK) analysis.
Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP62221 Plasma in the PKC + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for pharmacokinetic (PK) analysis.
Measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP622221 in the PKC412 + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2) Time: Cycle 1: day 22,Description: Blood samples were collected for pharmacokinetic (PK) analysis.
Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP52421 Plasma in the PKC + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for pharmacokinetic (PK) analysis.
Measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for PK analysis.
Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) Time: Cycle 1: days 21, 22, 28Description: Blood samples were collected for analysis.
Measure: Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) Time: Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15Description: Blood samples were collected for analysis.
Measure: Summary of CGP62221 Concentration (E2) Time: Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15Description: Blood samples were collected for analysis.
Measure: Summary of CGP52421 Concentration (E2) Time: Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15Description: TTP was defined as the time from first dose date to date of disease progression which is identified as study completion date for unsatisfactory treatment effect or date of death from any cause within the 28 day cutoff post treatment.
Measure: Time to Disease Progression (TTP) (Core) Time: from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003Description: Blood samples were collected for analysis.
Measure: Summary of Midostaurin Plasma Concentration (Core) Time: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,Description: Blood samples were collected for analysis.
Measure: Summary of CGP62221 Plasma Concentration (Core) Time: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,Description: Blood samples were collected for analysis.
Measure: Summary of CGP52421 Plasma Concentration (Core) Time: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,Description: TTP was defined as the time from the first dose date to the date of disease progression (defined as the study completion date for unsatisfactory treatment effect, date of response assessment of progressive disease, or date of death from any cause). One participant from the wild type 200 mg group did not have any assessment on treatment and therefore was not taken into account for TTP.
Measure: Time to Disease Progression (E1) Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004Description: OS was measured from the date of the first dose of treatment to the date of death from any cause or to the last date that the patient was known to be alive (a censored observation).
Measure: Overall Survival (OS) (E1) Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004Description: Duration of best clinical response was measured from the time that the measurement criteria were met for CR, PR, MR (with or without blast reduction) or BR until the first date that recurrent disease was documented (event) or until the date of last follow up.
Measure: Duration of Best Clinical Response (E1) Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004Description: Event-free survival was defined as the time from date of start of treatment to the date of death from any cause, treatment failure or relapse
Measure: Event-free Survival (E1) Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004Description: Blood samples were collected for analysis.
Measure: Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) Time: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)Description: Blood samples were collected for analysis.
Measure: Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) Time: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)Description: Blood samples were collected for analysis.
Measure: Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) Time: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)Description: Blood samples were collected for analysis.
Measure: Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) Time: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)Description: Blood samples were collected for analysis.
Measure: Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) Time: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)Description: Blood samples were collected for analysis.
Measure: Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) Time: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)Description: Best clinical response was defined as CR, PR, MR, MR+BR, or BR . CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.
Measure: Best Clinical Response (E2) Time: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008Description: TTP was defined as the time from the first dose date to the date of disease progression, which was defined as the study completion date for unsatisfactory treatment effect, the date of response assessment of progressive disease, or the date of death from any cause
Measure: Time to Disease Progression (E2) Time: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008Description: OS was measured from the date of the first dose of treatment to the date of death from any cause or the last date the patient was known to be alive (censored observation)
Measure: Overall Survival (E2) Time: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008Allocation: Randomized
Single Group Assignment
There is one SNP
2. Patients with a relevant FLT3-ITD mutation or D835Y point mutation 3. Patients at least 18 years or older 4. Patients with WHO performance status of 0 to 2 with a life expectancy of at least 3 months 5. Patients must not be treated within 4 weeks after any prior therapy 6. Written informed consent obtained according to local guidelines Exclusion criteria: Patients meeting any of the following criteria during screening will be excluded from entry into the study: 1. Patients who had prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously. --- D835Y ---