PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome (CPKC412A2104 Core); and PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome With Either Wild Type or Mutated FMS-like Tyrosine Kinase 3 (FLT3) (CPKC412A2104E1 and CPKC412A2104E2)

Phase 1

Completed

Conditions: Acute Myeloid Leukemia
Myelodysplastic Syndromes

Interventions: Drug: PKC412
Drug: Itraconazole

Registration Number: NCT00045942

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 144

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PKC412 (Core)	PKC412	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.
FLT3 mutated PKC412 100 mg/day (E1)	PKC412	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 mutated PKC412 200 mg/day (E1)	PKC412	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 wild type PKC+Itraconazole (E2)	PKC412	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.
FLT3 wild type PKC412 200 mg/day (E1)	PKC412	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 wild type PKC412 100 mg/day (E1)	PKC412	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 mutated PKC412 dose escalation	PKC412	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.
FLT3 mutated PKC+Itraconazole (E2)	PKC412	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.
FLT3 wild type PKC412 dose escalation (E2)	PKC412	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.
FLT3 mutated PKC+Itraconazole (E2)	Itraconazole	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.
FLT3 wild type PKC+Itraconazole (E2)	Itraconazole	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.

Primary Outcome Measures

Name	Time	Method
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 (E1)	days 1, 28
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.
Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)	days 1, 28
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.
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.
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.
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.

Secondary Outcome Measures

Name	Time	Method
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.
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)

Trial Locations

Locations (4): UCLA Medical Center
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Los Angeles, California, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States
New York Weill Cornell Medical Center
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New York, New York, United States