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)

Novartis

Status and phase

Completed

Phase 2

Phase 1

Conditions

Myelodysplastic Syndromes

Acute Myeloid Leukemia

Treatments

Drug: PKC412

Drug: Itraconazole

Study type

Interventional

Funder types

Industry

Identifiers

NCT00045942

CPKC412A2104

Details and patient eligibility

About

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.

Enrollment

144 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Single Group Assignment

Masking

None (Open label)

144 participants in 9 patient groups

PKC412 (Core)

Experimental group

Description:

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.

Treatment:

Drug: PKC412

FLT3 mutated PKC412 100 mg/day (E1)

Experimental group

Description:

Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Treatment:

Drug: PKC412

FLT3 mutated PKC412 200 mg/day (E1)

Experimental group

Description:

Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Treatment:

Drug: PKC412

FLT3 wild type PKC412 100 mg/day (E1)

Experimental group

Description:

Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Treatment:

Drug: PKC412

FLT3 wild type PKC412 200 mg/day (E1)

Experimental group

Description:

Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Treatment:

Drug: PKC412

FLT3 mutated PKC412 dose escalation

Experimental group

Description:

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.

Treatment:

Drug: PKC412

FLT3 mutated PKC+Itraconazole (E2)

Experimental group

Description:

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.

Treatment:

Drug: PKC412

Drug: Itraconazole

FLT3 wild type PKC412 dose escalation (E2)

Experimental group

Description:

Treatment:

Drug: PKC412

FLT3 wild type PKC+Itraconazole (E2)

Experimental group

Description:

Treatment: