Acute Myeloid Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
AML, MDS, high risk myelodysplastic syndrome
Brief summary
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.
Interventions
DRUGItraconazole
Itraconazole was commercially available.
DRUGPKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients: with AML who are not candidates for myelosuppressive chemotherapy or with AML who have relapsed disease or are refractory to standard therapy and not likely to require cytoreductive therapy within one month or with MDS subtypes refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T) or chronic myelomonocytic leukemia (CMML). 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. 2. Female patients who are pregnant or breast feeding, or adults of childbearing age not employing an effective method of birth control. 3. Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study. 4. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC412.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of CGP52421 Concentration (E2) | 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, 15 | Blood samples were collected for analysis. |
| Percent Decrease in Phospho-FLT3 Compared to Baseline (E2) | Days 1, 28 | — |
| 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) | Cycle 1: days 21, 22, 28 | Blood samples were collected for pharmacokinetic (PK) analysis. |
| Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1: days 21, 22, 28 | Blood samples were collected for pharmacokinetic (PK) analysis. |
| Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1: days 21, 22, 28 | Blood samples were collected for PK analysis. |
| 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) | Cycle 1: days 21, 22, 28 | Blood samples were collected for PK analysis. |
| Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) | Cycle 1: days 21 and 22 | Blood samples were collected for PK analysis. |
| 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) | Cycle 1: days 21, 22, 28 | Blood samples were collected for pharmacokinetic (PK) analysis. |
| Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1: days 21, 22, 28 | Blood samples were collected for pharmacokinetic (PK) analysis. |
| Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1: days 21, 22, 28 | Blood samples were collected for PK analysis. |
| 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) | Cycle 1: days 21, 22, 28 | Blood samples were collected for PK analysis. |
| Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2) | Cycle 1: day 22, | Blood samples were collected for PK analysis. |
| 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) | Cycle 1: days 21, 22, 28 | Blood samples were collected for pharmacokinetic (PK) analysis. |
| Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1: days 21, 22, 28 | Blood samples were collected for pharmacokinetic (PK) analysis. |
| Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1: days 21, 22, 28 | Blood samples were collected for PK analysis. |
| 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) | Cycle 1: days 21, 22, 28 | Blood samples were collected for PK analysis. |
| Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | 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, 15 | Blood samples were collected for analysis. |
| Summary of CGP62221 Concentration (E2) | 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, 15 | Blood samples were collected for analysis. |
| Number of Participants With Best Clinical Response (Core) | from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003 | 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. |
| Percent Decrease in Phospho-FLT3 Compared to Baseline (Core) | days 1, 28 | — |
| Number of Participants With Overall Clinical Response (E1) | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 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. |
| Percent Decrease in Phospho-FLT3 Compared to Baseline (E1) | days 1, 28 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Midostaurin Plasma Concentration (Core) | Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, | Blood samples were collected for analysis. |
| Summary of CGP62221 Plasma Concentration (Core) | Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, | Blood samples were collected for analysis. |
| Summary of CGP52421 Plasma Concentration (Core) | Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, | Blood samples were collected for analysis. |
| Time to Disease Progression (E1) | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 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. |
| Overall Survival (OS) (E1) | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 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). |
| Duration of Best Clinical Response (E1) | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 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. |
| Event-free Survival (E1) | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 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 |
| Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | 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) | Blood samples were collected for analysis. |
| Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | 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) | Blood samples were collected for analysis. |
| Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | 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) | Blood samples were collected for analysis. |
| Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | 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) | Blood samples were collected for analysis. |
| Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | 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) | Blood samples were collected for analysis. |
| Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | 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) | Blood samples were collected for analysis. |
| Best Clinical Response (E2) | date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 | 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. |
| Time to Disease Progression (E2) | date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 | 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 |
| Overall Survival (E2) | date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 | 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) |
| Time to Disease Progression (TTP) (Core) | from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003 | 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. |
Countries
United States
Participant flow
Recruitment details
In PKC412A2104 (Core), FLT3 mutated participants with AML or MDS received open-label PKC412. In PKC412A2104E1, FLT3 mutated participants and FLT3 wild type participants were randomized to receive either PKC412 50 mg bid or PKC412 100 mg bid.
Pre-assignment details
In PKC412A2104E2, participants were alternately assigned to the regimens, beginning with the first enrolled into the intra-patient dose escalation arm and the next enrolled into the PKC412 + itraconazole arm. Of the 16 participants enrolled in the PKC412 dose escalation arm, 14 were newly enrolled, and 2 were transitioned from PKC412A2104E1.
Participants by arm
| Arm | Count |
|---|---|
| PKC412 in FLT3 Mutated Participants (Core) Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | 20 |
| FLT3 Mutated PKC412 100 mg/Day (E1) Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | 18 |
| FLT3 Mutated PKC412 200 mg/Day (E1) Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | 17 |
| FLT3 Wild Type PKC412 100 mg/Day (E1) Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | 33 |
| FLT3 Wild Type PKC412 200 mg/Day (E1) Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | 27 |
| FLT3 Mutated PKC412 Dose Escalation (E2) Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity. | 8 |
| FLT3 Mutated PKC+Itraconazole (E2) Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent. | 7 |
| FLT3 Wild Type PKC412 Dose Escalation (E2) Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity. | 6 |
| FLT3 Wild Type PKC+Itraconazole (E2) Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent. | 6 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| PKC412A2104 (Core) | Adverse Event | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PKC412A2104 (Core) | Death | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PKC412A2104 (Core) | Lack of Efficacy | 13 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PKC412A2104 (Core) | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PKC412A2104E1 | Abnormal laboratory value | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PKC412A2104E1 | Adverse Event | 0 | 1 | 1 | 3 | 6 | 0 | 0 | 0 | 0 |
| PKC412A2104E1 | Condition no longer requires study drug | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| PKC412A2104E1 | Death | 0 | 4 | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| PKC412A2104E1 | Enrolled into PKC412A2104E2 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| PKC412A2104E1 | Lack of Efficacy | 0 | 11 | 11 | 23 | 17 | 0 | 0 | 0 | 0 |
| PKC412A2104E1 | Withdrawal by Subject | 0 | 0 | 2 | 5 | 2 | 0 | 0 | 0 | 0 |
| PKC412A2104E2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 4 | 3 | 1 | 0 |
| PKC412A2104E2 | Death | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 0 | 0 |
| PKC412A2104E2 | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 3 | 2 | 2 | 6 |
| PKC412A2104E2 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
| PKC412A2104E2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | FLT3 Wild Type PKC412 200 mg/Day (E1) | FLT3 Mutated PKC+Itraconazole (E2) | FLT3 Wild Type PKC412 Dose Escalation (E2) | FLT3 Wild Type PKC+Itraconazole (E2) | Total | PKC412 in FLT3 Mutated Participants (Core) | FLT3 Mutated PKC412 100 mg/Day (E1) | FLT3 Mutated PKC412 200 mg/Day (E1) | FLT3 Wild Type PKC412 100 mg/Day (E1) | FLT3 Mutated PKC412 Dose Escalation (E2) |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 19 Participants | 2 Participants | 6 Participants | 6 Participants | 86 Participants | 9 Participants | 7 Participants | 9 Participants | 26 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 5 Participants | 0 Participants | 0 Participants | 56 Participants | 11 Participants | 11 Participants | 8 Participants | 7 Participants | 6 Participants |
| Sex: Female, Male Female | 15 Participants | 3 Participants | 4 Participants | 4 Participants | 66 Participants | 6 Participants | 5 Participants | 9 Participants | 17 Participants | 3 Participants |
| Sex: Female, Male Male | 12 Participants | 4 Participants | 2 Participants | 2 Participants | 76 Participants | 14 Participants | 13 Participants | 8 Participants | 16 Participants | 5 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 | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 20 | 17 / 18 | 16 / 17 | 32 / 33 | 27 / 27 | 9 / 9 | 6 / 7 | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 12 / 20 | 16 / 18 | 14 / 17 | 22 / 33 | 19 / 27 | 7 / 9 | 6 / 7 | 5 / 7 | 3 / 6 |
Outcome results
Primary
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)
Blood samples were collected for pharmacokinetic (PK) analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 21 (n=9) | 40258.65 h*ng/ml | Standard Deviation 9747.374 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 22 (n=7) | 42950.76 h*ng/ml | Standard Deviation 8604.972 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 28 (n=7) | 49758.77 h*ng/ml | Standard Deviation 7733.621 |
Primary
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)
Blood samples were collected for pharmacokinetic (PK) analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 21 (n=8) | 30217.82 h*ng/ml | Standard Deviation 16502.9 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 22 (n=7) | 23824.69 h*ng/ml | Standard Deviation 13300.69 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 28 (n=7) | 31545.54 h*ng/ml | Standard Deviation 12453.16 |
Primary
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)
Blood samples were collected for pharmacokinetic (PK) analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 21 (n=9) | 22261.53 h*ng/ml | Standard Deviation 11984.6 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 22 (n=10) | 37578.85 h*ng/ml | Standard Deviation 44330.7 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 28 (n=7) | 35630.45 h*ng/ml | Standard Deviation 23993.2 |
Primary
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)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 21 (n=10) | 38899.84 h*ng/ml | Standard Deviation 7616.481 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 22 (n=10) | 41035.50 h*ng/ml | Standard Deviation 10807.22 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 28 (n=8) | 44447.05 h*ng/ml | Standard Deviation 8906.006 |
Primary
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)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 21 (n=10) | 31699.93 h*ng/ml | Standard Deviation 15573.87 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 22 (n=10) | 31182.90 h*ng/ml | Standard Deviation 17380.39 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 28 (n=8) | 26688.60 h*ng/ml | Standard Deviation 10901.4 |
Primary
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)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 21 (n=10) | 32120.58 h*ng/ml | Standard Deviation 35792.2 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 22 (n=10) | 34684.6 h*ng/ml | Standard Deviation 37084.9 |
| PKC412 in FLT3 Mutated Participants (Core) | 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) | Cycle 1, day 28, (n=8) | 33020.17 h*ng/ml | Standard Deviation 17206.3 |
Primary
Number of Participants With Best Clinical Response (Core)
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.
Time frame: from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003
Population: Core primary efficacy population: The core primary efficacy population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Number of Participants With Best Clinical Response (Core) | 0 Participants |
Primary
Number of Participants With Overall Clinical Response (E1)
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.
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Population: E1 primary efficacy population: all participants who received at least one dose of study medication, completed at least 8 days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Number of Participants With Overall Clinical Response (E1) | Blast response | 11 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Number of Participants With Overall Clinical Response (E1) | Partial response | 0 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Number of Participants With Overall Clinical Response (E1) | Overall response | 12 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Number of Participants With Overall Clinical Response (E1) | Minor response | 1 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Number of Participants With Overall Clinical Response (E1) | Complete response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Minor response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Blast response | 12 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Overall response | 13 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Partial response | 1 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Complete response | 0 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Minor response | 6 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Complete response | 0 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Partial response | 0 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Blast response | 15 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Overall response | 21 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Blast response | 8 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Partial response | 0 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Complete response | 0 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Minor response | 3 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Number of Participants With Overall Clinical Response (E1) | Overall response | 11 Participants |
Primary
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2)
Blood samples were collected for pharmacokinetic (PK) analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 21 (n=10) | 4173.00 ng/ml | Standard Deviation 985.473 |
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 22 (n=10) | 4293.00 ng/ml | Standard Deviation 1292.38 |
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 28 (n=8) | 4875.00 ng/ml | Standard Deviation 1376.382 |
Primary
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2)
Blood samples were collected for pharmacokinetic (PK) analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 21 (n=10) | 3259.30 ng/ml | Standard Deviation 1747.923 |
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 22 (n=10) | 3221.40 ng/ml | Standard Deviation 1980.217 |
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 28 (n=8) | 3032.25 ng/ml | Standard Deviation 1975.371 |
Primary
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2)
Blood samples were collected for pharmacokinetic (PK) analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1 , day 21 (n=10) | 3945.00 ng/ml | Standard Deviation 4440.238 |
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 22 (n=10) | 3968.70 ng/ml | Standard Deviation 4047.498 |
| PKC412 in FLT3 Mutated Participants (Core) | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) | Cycle 1, day 28 (n=8) | 3931.25 ng/ml | Standard Deviation 2638.135 |
Primary
Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)
Time frame: days 1, 28
Population: This outcome measure was not analyzed. Assessment of FLT3 autophosphorylation in leukemic blasts was not possible at the planned time points because the blast reduction was rapid and occurred during the first week in some participants. Thus, by Day 28, the blast count in some participants were too low for autophosphorylation to be measured.
Primary
Percent Decrease in Phospho-FLT3 Compared to Baseline (E1)
Time frame: days 1, 28
Population: The analyses for this outcome measure were not performed due to technical challenges in measuring phosphorylated FLT3 in patient blast samples in an ex vivo setting.
Primary
Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)
Time frame: Days 1, 28
Population: The analyses for this outcome measure were not performed due to technical challenges in measuring phosphorylated FLT3 in patient blast samples in an ex vivo setting.
Primary
Summary of CGP52421 Concentration (E2)
Blood samples were collected for analysis.
Time frame: 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, 15
Population: The PK analysis set of the FLT3 mutated PKC412 dose escalation and FLT3 wild type PKC412 dose escalation combined arms, which consisted of the 14 newly enrolled participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 15 (n=6) | 3845.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 1 (n=7) | 0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 2 (24 hr post day 1) (n=12) | 684.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 3 (n=12) | 1185.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 8 (n=8) | 2835.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 16 (24 hr post day 15) (n=6) | 3830.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 17 (n=5) | 3620.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 1, day 22 (n=5) | 4470.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 2, day 1 (n=4) | 4915.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 2, day 2 (24 hr post day 1) (n=4) | 4455.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 2, day 3 (n=4) | 4470.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 2, day 8 (n=4) | 4860.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Concentration (E2) | Cycle 2, day 15 (n=3) | 4030.0 ng/ml |
Primary
Summary of CGP62221 Concentration (E2)
Blood samples were collected for analysis.
Time frame: 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, 15
Population: The PK analysis set of the FLT3 mutated PKC412 dose escalation and FLT3 wild type PKC412 dose escalation combined arms, which consisted of the 14 newly enrolled participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 2, day 15 (n=3) | 1740.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 1 (n=7) | 0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 2 (24 hr post day 1) (n=12) | 1320.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 3 (n=12) | 2750.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 8 (n=8) | 2380.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 15 (n=6) | 1505.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 16 (24 hr post day 15) (n=6) | 1425.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 17 (n=5) | 1480.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 1, day 22 (n=5) | 1520.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 2, day 1 (n=4) | 1545.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 2, day 2 (24 hr post day 1) (n=4) | 1945.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 2, day 3 (n=4) | 2070.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Concentration (E2) | Cycle 2, day 8 (n=4) | 2030.0 ng/ml |
Primary
Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2)
Blood samples were collected for analysis.
Time frame: 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, 15
Population: The PK analysis set of the FLT3 mutated PKC412 dose escalation and FLT3 wild type PKC412 dose escalation combined arms, which consisted of the 14 newly enrolled participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 1 (=7) | 0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 2 (24 hours post day 1) (n=12) | 2565.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 3 (n=12) | 3100.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 8 (n=8) | 1640.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 15 (n=6) | 744.5 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 16 (24 hr post day 15) (n=6) | 836.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 17 (n=5) | 800.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 1, day 22 (n=5) | 1410.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 2, day 1 (n=4) | 772.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 2, day 2 (24 hr post day 1) (n=4) | 1141.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 2, day3 (n=4) | 1295.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 2, day 8 (n=4) | 1210.0 ng/ml |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Cycle 2, day 15 (n=3) | 834.0 ng/ml |
Primary
Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: day 22,
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For this end point, 4 participants with non-missing values were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2) | 14.37 hour | Standard Deviation 6.743 |
Primary
Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: days 21 and 22
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) | Cycle 1, day 21 (n=6) | 18.13 hour | Standard Deviation 13.505 |
| PKC412 in FLT3 Mutated Participants (Core) | Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) | Cycle 1, day 22 (n=8) | 13.23 hour | Standard Deviation 6.346 |
Primary
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 21 (n=10) | 3.5 hour |
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 22 (n=10) | 2.1 hour |
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 28 (n=8) | 2.2 hour |
Primary
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 21 (n=10) | 3.7 hour |
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 22 (n=10) | 2.3 hour |
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 28 (n=8) | 3.3 hour |
Primary
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Time frame: Cycle 1: days 21, 22, 28
Population: The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 21 (n=10) | 1.6 hour |
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 22 (n=10) | 1.9 hour |
| PKC412 in FLT3 Mutated Participants (Core) | Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) | Cycle 1, day 28 (n=8) | 2.2 hour |
Secondary
Best Clinical Response (E2)
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.
Time frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Population: The primary efficacy population, which included all participants, who received at least one dose of study drug and who completed at least 8 days of treatment in Cycle 1, unless they discontinued due to progressive disease and/or death due to any cause, and who did not experience any protocol violations, was analyzed..
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Best Clinical Response (E2) | Blast response | 4 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Best Clinical Response (E2) | Partial response | 0 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Best Clinical Response (E2) | Best clinical response | 5 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Best Clinical Response (E2) | Minor response | 0 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Best Clinical Response (E2) | Minor response and blast response | 1 Participants |
| PKC412 in FLT3 Mutated Participants (Core) | Best Clinical Response (E2) | Complete response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Minor response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Complete response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Blast response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Minor response and blast response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Best clinical response | 0 Participants |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Partial response | 0 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Best Clinical Response (E2) | Best clinical response | 2 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Best Clinical Response (E2) | Partial response | 0 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Best Clinical Response (E2) | Minor response and blast response | 2 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Best Clinical Response (E2) | Minor response | 0 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Best Clinical Response (E2) | Complete response | 0 Participants |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Best Clinical Response (E2) | Blast response | 0 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Best clinical response | 4 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Complete response | 1 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Partial response | 0 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Minor response | 1 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Minor response and blast response | 1 Participants |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Best Clinical Response (E2) | Blast response | 1 Participants |
Secondary
Duration of Best Clinical Response (E1)
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.
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Population: Responders from the PEP; PEP defined as all patients who received at least 1 dose of study medication, completed at least 8 days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Duration of Best Clinical Response (E1) | 57.0 days |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Duration of Best Clinical Response (E1) | 29.0 days |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Duration of Best Clinical Response (E1) | 56.0 days |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Duration of Best Clinical Response (E1) | 58.0 days |
Secondary
Event-free Survival (E1)
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
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Population: Primary efficacy population: defined as all patients who received at least 1 dose of study medication, completed at least eight days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Event-free Survival (E1) | 60.0 days |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Event-free Survival (E1) | 50.0 days |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Event-free Survival (E1) | 58.0 days |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Event-free Survival (E1) | 1.0 days |
Secondary
Overall Survival (E2)
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)
Time frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Population: The primary efficacy population, which included all participants, who received at least one dose of study drug and who completed at least 8 days of treatment in Cycle 1, unless they discontinued due to progressive disease and/or death due to any cause, and who did not experience any protocol violations, was analyzed..
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Overall Survival (E2) | 116.0 days |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Overall Survival (E2) | 75.0 days |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Overall Survival (E2) | 372.0 days |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Overall Survival (E2) | 220.0 days |
Secondary
Overall Survival (OS) (E1)
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).
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Population: Primary efficacy population: defined as all patients who received at least 1 dose of study medication, completed at least eight days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Overall Survival (OS) (E1) | 99.0 days |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Overall Survival (OS) (E1) | 93.0 days |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Overall Survival (OS) (E1) | 145.0 days |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Overall Survival (OS) (E1) | 159.0 days |
Secondary
Summary of CGP52421 Plasma Concentration (Core)
Blood samples were collected for analysis.
Time frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Population: The Core PK analysis set, which consisted of 15 participants, were considered for the analysis. For each time point, only participants of the PK set who had non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration (Core) | Cycle 1, day 1 (24 hour) (n=10) | 951.70 ng/ml | Standard Deviation 297.866 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration (Core) | Cycle 1, day 3 (n=7) | 1846.57 ng/ml | Standard Deviation 657.472 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration (Core) | Cycle 1, day 8 (n=9) | 6342.22 ng/ml | Standard Deviation 2586.44 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration (Core) | Cycle 2, day 1 (n=6) | 12978.33 ng/ml | Standard Deviation 4036.436 |
Secondary
Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1)
Blood samples were collected for analysis.
Time frame: 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)
Population: The PK population of the mutated PKC412 200 mg/day and wild type PKC412 200 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (0h) (n=38) | 0.000 ng/ml | Standard Deviation 0 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (4h) (n=34) | 257.391 ng/ml | Standard Deviation 148.642 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (24h) (n=36) | 666.194 ng/ml | Standard Deviation 313.577 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 3 (0h) (n=29) | 1394.062 ng/ml | Standard Deviation 653.2943 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 8 (0h) (n=24) | 4447.500 ng/ml | Standard Deviation 1359.192 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 2, day 1 (0h) (n=15) | 9196.667 ng/ml | Standard Deviation 3248.59 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 3, day 2 (0h) (n=6) | 8811.667 ng/ml | Standard Deviation 3376.172 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 4, day 1 (0h) (n=6) | 6266.667 ng/ml | Standard Deviation 3895.452 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 5, day 1 (0h) (n4) | 7845.000 ng/ml | Standard Deviation 4078.313 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 6, day 1 (0h) (n=4) | 8710.000 ng/ml | Standard Deviation 4890.774 |
Secondary
Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1)
Blood samples were collected for analysis.
Time frame: 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)
Population: The PK population of the mutated PKC412 100 mg/day and wild type PKC412 100 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 1 (0h) (n=41) | 0.000 ng/ml | Standard Deviation 0 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 1 (4h) (n=38) | 203.013 ng/ml | Standard Deviation 121.3817 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 1 (24h) (n=39) | 436.282 ng/ml | Standard Deviation 210.1306 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Day 1, day 3 (0h) (n=34) | 1188.359 ng/ml | Standard Deviation 1833.644 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 8 (0h) (n=30) | 2840.833 ng/ml | Standard Deviation 1158.132 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 2, day 1 (0h) (n=22) | 6467.591 ng/ml | Standard Deviation 3434.776 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 3, day 1 (0h) (n=12) | 8175.000 ng/ml | Standard Deviation 4851.968 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 4, day 1 (0h) (n=4) | 6205.000 ng/ml | Standard Deviation 1619.084 |
Secondary
Summary of CGP62221 Plasma Concentration (Core)
Blood samples were collected for analysis.
Time frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Population: The Core PK analysis set, which consisted of 15 participants, were considered for the analysis. For each time point, only participants of the PK set who had non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration (Core) | Cycle 1, day 1 (24 hour) (n=10) | 1636.00 ng/ml | Standard Deviation 612.938 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration (Core) | Cycle 1, day 3 (n=7) | 3143.71 ng/ml | Standard Deviation 1147.407 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration (Core) | Cycle 1, day 8 (n=9) | 4873.33 ng/ml | Standard Deviation 3421.593 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration (Core) | Cycle 2, day 1 (n=6) | 2816.67 ng/ml | Standard Deviation 2095.85 |
Secondary
Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1)
Blood samples were collected for analysis.
Time frame: 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)
Population: The PK population of the mutated PKC412 200 mg/day and wild type PKC412 200 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (0h) (n=39) | 0.000 ng/ml | Standard Deviation 0 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (4h) (n=34) | 471.635 ng/ml | Standard Deviation 342.785 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (24h) (n=36) | 1134.764 ng/ml | Standard Deviation 655.1779 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 3 (0h) (n=29) | 1944.069 ng/ml | Standard Deviation 1049.77 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 8 (0h) (n=24) | 2898.708 ng/ml | Standard Deviation 1876.446 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 2, day 1 (0h) (n=15) | 1828.667 ng/ml | Standard Deviation 650.1524 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 3, day 2 (0h) (n=6) | 1258.333 ng/ml | Standard Deviation 289.0271 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 4, day 1 (0h) (n=6) | 1602.950 ng/ml | Standard Deviation 1071.167 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 5, day 1 (0h) (n4) | 1111.250 ng/ml | Standard Deviation 357.8728 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 6, day 1 (0h) (n=4) | 1662.500 ng/ml | Standard Deviation 864.4603 |
Secondary
Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1)
Blood samples were collected for analysis.
Time frame: 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)
Population: The PK population of the mutated PKC412 100 mg/day and wild type PKC412 100 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 1 (0h) (n=44) | 0.000 ng/ml | Standard Deviation 0 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 1 (4h) (n=38) | 367.079 ng/ml | Standard Deviation 220.2728 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 1 (24h) (n=39) | 808.182 ng/ml | Standard Deviation 375.4818 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 3 (0h) (n=34) | 1400.476 ng/ml | Standard Deviation 681.9106 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 1, day 8 (0h) (n=30) | 2868.933 ng/ml | Standard Deviation 1723.985 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 2, day 1 (0h) (n=22) | 1930.000 ng/ml | Standard Deviation 1241.98 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 3, day 1 (0h) (n=12) | 1971.500 ng/ml | Standard Deviation 1519.628 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Cycle 4, day 1 (0h) (n=4) | 1207.500 ng/ml | Standard Deviation 310.5238 |
Secondary
Summary of Midostaurin Plasma Concentration (Core)
Blood samples were collected for analysis.
Time frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Population: The Core PK analysis set, which consisted of 15 participants, was considered for the analysis. For each time point, only participants of the PK set who had non-missing values were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Plasma Concentration (Core) | Cycle 1, day 1(24 hour) (n=10) | 3801.0 ng/ml | Standard Deviation 2529.069 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Plasma Concentration (Core) | Cycle 1, day 3 (n=7) | 7152.86 ng/ml | Standard Deviation 4254.173 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Plasma Concentration (Core) | Cycle 1, day 8 (n=9) | 5154.44 ng/ml | Standard Deviation 5004.511 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of Midostaurin Plasma Concentration (Core) | Cycle 2, day 1 (n=6) | 1873.17 ng/ml | Standard Deviation 1521.685 |
Secondary
Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1)
Blood samples were collected for analysis.
Time frame: 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)
Population: The PK population of the mutated PKC412 200 mg/day and wild type PKC412 200 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (0h) (n=38) | 0.000 ng/ml | Standard Deviation 0 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (4h) (n=34) | 2087.088 ng/ml | Standard Deviation 1087.277 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 1 (24h) (n=36) | 2849.731 ng/ml | Standard Deviation 2150.176 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 3 (0h) (n=29) | 3756.483 ng/ml | Standard Deviation 2549.759 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 1, day 8 (0h) (n=24) | 4447.583 ng/ml | Standard Deviation 4233.285 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 2, day 1 (0h) (n=15) | 1226.333 ng/ml | Standard Deviation 894.1562 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 3, day 2 (0h) (n=6) | 754.500 ng/ml | Standard Deviation 264.686 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 4, day 1 (0h) (n=6) | 1187.167 ng/ml | Standard Deviation 1026.004 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 5, day 1 (0h) (n=4) | 572.250 ng/ml | Standard Deviation 314.7405 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Cycle 6, day 1 (0h) (n=4) | 1433.250 ng/ml | Standard Deviation 1670.029 |
Secondary
Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1)
Blood samples were collected for analysis.
Time frame: 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)
Population: The PK population of the mutated PKC412 100 mg/day and wild type PKC412 100 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 1, day 1 (0h) (n=43) | 0.000 ng/ml | Standard Deviation 0 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 1, day 1 (4h) (n=38) | 1198.000 ng/ml | Standard Deviation 522.4766 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 1, day 1 (24h) (n=39) | 1735.974 ng/ml | Standard Deviation 1161.933 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 1, day 3 (0h) (n=34) | 2585.471 ng/ml | Standard Deviation 1843.852 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 1, day 8 (0h) (n=30) | 3576.467 ng/ml | Standard Deviation 3263.112 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 2, day 1 (0h) (n=22) | 1756.500 ng/ml | Standard Deviation 1695.327 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 3, day 1 (0h) (n=12) | 2038.417 ng/ml | Standard Deviation 2079.252 |
| PKC412 in FLT3 Mutated Participants (Core) | Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Cycle 4, day 1 (0h) (n=4) | 820.750 ng/ml | Standard Deviation 565.0247 |
Secondary
Time to Disease Progression (E1)
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.
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Population: Primary efficacy population: defined as all patients who received at least 1 dose of study medication, completed at least eight days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Time to Disease Progression (E1) | 77.0 days |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Time to Disease Progression (E1) | 50.0 days |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Time to Disease Progression (E1) | 62.0 days |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Time to Disease Progression (E1) | 54.0 days |
Secondary
Time to Disease Progression (E2)
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
Time frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Population: The primary efficacy population, which included all participants, who received at least one dose of study drug and who completed at least 8 days of treatment in Cycle 1, unless they discontinued due to progressive disease and/or death due to any cause, and who did not experience any protocol violations, was analyzed..
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Time to Disease Progression (E2) | 49.0 days |
| FLT3 Mutated PKC412 200 mg/Day (E1) | Time to Disease Progression (E2) | 26.0 days |
| FLT3 Wild Type PKC412 100 mg/Day (E1) | Time to Disease Progression (E2) | 169.0 days |
| FLT3 Wild Type PKC412 200 mg/Day (E1) | Time to Disease Progression (E2) | 78.0 days |
Secondary
Time to Disease Progression (TTP) (Core)
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.
Time frame: from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003
Population: Core primary efficacy population: The core primary efficacy population included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PKC412 in FLT3 Mutated Participants (Core) | Time to Disease Progression (TTP) (Core) | 63.0 days |