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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 144
- 试验地点
- 4
- 主要终点
- Number of Participants With Best Clinical Response (Core)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
PKC412 (Core)
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.
干预措施: PKC412 (Drug)
FLT3 mutated PKC412 100 mg/day (E1)
Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
干预措施: PKC412 (Drug)
FLT3 mutated PKC412 200 mg/day (E1)
Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
干预措施: PKC412 (Drug)
FLT3 wild type PKC412 100 mg/day (E1)
Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
干预措施: PKC412 (Drug)
FLT3 wild type PKC412 200 mg/day (E1)
Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
干预措施: PKC412 (Drug)
FLT3 mutated PKC412 dose escalation
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.
干预措施: PKC412 (Drug)
FLT3 mutated PKC+Itraconazole (E2)
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.
干预措施: Itraconazole (Drug)
FLT3 mutated PKC+Itraconazole (E2)
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.
干预措施: PKC412 (Drug)
FLT3 wild type PKC412 dose escalation (E2)
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.
干预措施: PKC412 (Drug)
FLT3 wild type PKC+Itraconazole (E2)
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.
干预措施: Itraconazole (Drug)
FLT3 wild type PKC+Itraconazole (E2)
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.
干预措施: PKC412 (Drug)
结局指标
主要结局
Number of Participants With Best Clinical Response (Core)
时间窗: 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)
时间窗: 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)
时间窗: Cycle 1: days 21, 22, 28
Blood samples were collected for PK analysis.
Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)
时间窗: days 1, 28
Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: Cycle 1: days 21, 22, 28
Blood samples were collected for PK analysis.
Number of Participants With Overall Clinical Response (E1)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: Cycle 1: days 21, 22, 28
Blood samples were collected for PK analysis.
Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2)
时间窗: 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)
时间窗: 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)
时间窗: 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.
次要结局
- Time to Disease Progression (TTP) (Core)(from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003)
- Summary of Midostaurin Plasma Concentration (Core)(Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,)
- Summary of CGP62221 Plasma Concentration (Core)(Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,)
- Summary of CGP52421 Plasma Concentration (Core)(Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,)
- Time to Disease Progression (E1)(from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004)
- Overall Survival (OS) (E1)(from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004)
- Duration of Best Clinical Response (E1)(from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004)
- Event-free Survival (E1)(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)(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)(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)(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)(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)(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)(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)(date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008)
- Time to Disease Progression (E2)(date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008)
- Overall Survival (E2)(date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008)