Clinical trial NCT00045942: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Myelodysplastic Syndromes
Keywords: AML
MDS
high risk myelodysplastic syndrome
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2002-09-18
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Best Clinical Response (Core)
timeFrame: from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003
measure: Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)
timeFrame: days 1, 28
measure: Number of Participants With Overall Clinical Response (E1)
timeFrame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
measure: Percent Decrease in Phospho-FLT3 Compared to Baseline (E1)
timeFrame: days 1, 28
measure: Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)
timeFrame: Days 1, 28
measure: 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)
timeFrame: Cycle 1: days 21, 22, 28
measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2)
timeFrame: Cycle 1: days 21, 22, 28
measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)
timeFrame: Cycle 1: days 21, 22, 28
measure: 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)
timeFrame: Cycle 1: days 21, 22, 28
measure: Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2)
timeFrame: Cycle 1: days 21 and 22
measure: 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)
timeFrame: Cycle 1: days 21, 22, 28
measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2)
timeFrame: Cycle 1: days 21, 22, 28
measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2)
timeFrame: Cycle 1: days 21, 22, 28
measure: 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)
timeFrame: Cycle 1: days 21, 22, 28
measure: Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2)
timeFrame: Cycle 1: day 22,
measure: 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)
timeFrame: Cycle 1: days 21, 22, 28
measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2)
timeFrame: Cycle 1: days 21, 22, 28
measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)
timeFrame: Cycle 1: days 21, 22, 28
measure: 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)
timeFrame: Cycle 1: days 21, 22, 28
measure: Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2)
timeFrame: 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
measure: Summary of CGP62221 Concentration (E2)
timeFrame: 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
measure: Summary of CGP52421 Concentration (E2)
timeFrame: 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 outcomes:
measure: Time to Disease Progression (TTP) (Core)
timeFrame: from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003
measure: Summary of Midostaurin Plasma Concentration (Core)
timeFrame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
measure: Summary of CGP62221 Plasma Concentration (Core)
timeFrame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
measure: Summary of CGP52421 Plasma Concentration (Core)
timeFrame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
measure: Time to Disease Progression (E1)
timeFrame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
measure: Overall Survival (OS) (E1)
timeFrame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
measure: Duration of Best Clinical Response (E1)
timeFrame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
measure: Event-free Survival (E1)
timeFrame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
measure: Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1)
timeFrame: 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)
measure: Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1)
timeFrame: 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)
measure: Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1)
timeFrame: 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)
measure: Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1)
timeFrame: 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)
measure: Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1)
timeFrame: 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)
measure: Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1)
timeFrame: 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)
measure: Best Clinical Response (E2)
timeFrame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
measure: Time to Disease Progression (E2)
timeFrame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
measure: Overall Survival (E2)
timeFrame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: New York Weill Cornell Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: