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)

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)

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.

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.