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)

Study Overview
=================
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.

Official Title
-----------------
An Open-label Phase II (Proof of Concept (POC)) Trial of PKC412 Monotherapy in Participants With Acute Myeloid Leukemia (AML) and Participants With High Risk Myelodysplastic Syndrome (MDS) (CPKC412A2104 Core); An Open-label, Randomized Phase II POC Trial in PKC412 in Participants With AML and Participants With High Risk MDS With Either Wild Type or Mutated FLT3 (CPKC412A2104E1); and An Open-label, Randomized Phase 1/II POC Trial in PKC412 in Participants With AML and Participants With High Risk MDS With Either Wild Type or Mutated FLT3 (CPKC412A2104E2)

Conditions
-----------------
Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: Itraconazole
* Drug: PKC412


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: 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). Patients with a relevant FLT3-ITD mutation or D835Y point mutation Patients at least 18 years or older Patients with WHO performance status of 0 to 2 with a life expectancy of at least 3 months Patients must not be treated within 4 weeks after any prior therapy 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: Patients who had prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously. Female patients who are pregnant or breast feeding, or adults of childbearing age not employing an effective method of birth control. Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC412.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PKC412 (Core)<br>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. | Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 mutated PKC412 100 mg/day (E1)<br>Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 mutated PKC412 200 mg/day (E1)<br>Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 wild type PKC412 100 mg/day (E1)<br>Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 wild type PKC412 200 mg/day (E1)<br>Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. | Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 mutated PKC412 dose escalation<br>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. | Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 mutated PKC+Itraconazole (E2)<br>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. | Drug: Itraconazole<br>* Itraconazole was commercially available.<br>Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 wild type PKC412 dose escalation (E2)<br>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. | Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|
| Experimental: FLT3 wild type PKC+Itraconazole (E2)<br>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. | Drug: Itraconazole<br>* Itraconazole was commercially available.<br>Drug: PKC412<br>* PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.<br>* Other names: Midostaurin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003 | 
| Percent Decrease in Phospho-FLT3 Compared to Baseline (Core) |  | days 1, 28 | 
| 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. | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 
| Percent Decrease in Phospho-FLT3 Compared to Baseline (E1) |  | 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) | Blood samples were collected for pharmacokinetic (PK) analysis. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 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) | Blood samples were collected for PK analysis. | Cycle 1: days 21, 22, 28 | 
| Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) | Blood samples were collected for PK analysis. | Cycle 1: days 21 and 22 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2) | Blood samples were collected for PK analysis. | Cycle 1: day 22, | 
| 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. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| 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. | Cycle 1: days 21, 22, 28 | 
| Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) | Blood samples were collected for analysis. | 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 | 
| Summary of CGP62221 Concentration (E2) | Blood samples were collected for analysis. | 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 | 
| Summary of CGP52421 Concentration (E2) | Blood samples were collected for analysis. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003 | 
| Summary of Midostaurin Plasma Concentration (Core) | Blood samples were collected for analysis. | Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, | 
| Summary of CGP62221 Plasma Concentration (Core) | Blood samples were collected for analysis. | Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, | 
| Summary of CGP52421 Plasma Concentration (Core) | Blood samples were collected for analysis. | Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, | 
| 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. | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 
| 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). | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 
| 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. | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 
| 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 | from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 | 
| Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) | Blood samples were collected for analysis. | 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) | 
| Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) | Blood samples were collected for analysis. | 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) | 
| Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) | Blood samples were collected for analysis. | 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) | 
| Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) | Blood samples were collected for analysis. | 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) | 
| Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) | Blood samples were collected for analysis. | 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) | 
| Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) | Blood samples were collected for analysis. | 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) | 
| 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. | date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 | 
| 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 | date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 | 
| 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) | date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML, MDS, high risk myelodysplastic syndrome