A Phase III, Randomized, Double-blind Study of Chemotherapy With Daunorubicin or Idarubicin and Cytarabine for Induction and Intermediate Dose Cytarabine for Consolidation Plus Midostaurin (PKC412) or Chemotherapy Plus Placebo in Newly Diagnosed Patients With FLT-3 Mutation Negative Acute Myeloid Leukemia (AML)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 511
- 试验地点
- 4
- 主要终点
- Event Free Survival (EFS)
研究概览
简要总结
The purpose of this study was to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML patients with the FLT3-mutations but also in FLT3-MN (SR<0.05) AML (FLT3 mutant to wild type signal ratio below the 0.05 clinical cut-off).
This study evaluated the efficacy and safety of midostaurin in combination with daunorubicin or idarubicin and cytarabine for induction and intermediate-dose cytarabine for consolidation, and midostaurin single agent post-consolidation therapy in newly diagnosed patients with FLT3-MN (SR<0.05) AML.
详细描述
This was a multi-center, multinational, randomized, double-blind Phase III study using a group sequential design. Subjects were stratified according to age (<60 vs. ≥ 60 years). Subjects within each stratum were randomized in a 1:1 ratio into one of two treatment arms: Midostaurin + chemotherapy 'or' Placebo + chemotherapy.
The study consisted of the following phases:
Screening/randomization phase: Subjects had to sign informed consent form before screening for enrollment. Subjects started chemotherapy at day 1 and were randomized at day 8.
Induction phase: All subjects received at least one cycle (28 days) of induction therapy with continuous infusion cytarabine (D1 - D7) and daunorubicin or idarubicin (D1 - D3) (induction 1). Subjects who did not achieve CR or CRi with adequate blood count recovery after Induction 1 received a second cycle with intermediate-dose cytarabine (D1 - D3) and daunorubicin or idarubicin (D1 - D3) (induction 2). Subjects who did not achieve CR or CRi with adequate blood recovery after induction 2 discontinued study treatment and were followed for survival.
Consolidation phase: Subjects who achieved CR or CRi with adequate blood count recovery after induction with one or two cycles of induction proceeded to consolidation therapy with either 3 or 4 cycles respectively of intermediate-dose cytarabine (D1 - D3), or to Hematopoietic Stem Cells Transplantation (HSCT) with or without preceding consolidation cycles.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Diagnosis of AML (≥20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL with PML-RARA are not eligible.
- •Suitability for intensive induction chemotherapy in the judgment of the investigator
- •Documented absence of an ITD and TKD activating mutation at codons D835 and I836 in the FLT3 gene, as determined by analysis in a Novartis designated laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type signal ratio
- •Age ≥18 years
- •Laboratory values that indicate adequate organ function assessed locally at the screening visit
排除标准
- •Central nervous system (CNS) leukemia
- •Therapy-related secondary AML
- •Isolated extramedullary leukemia
- •Prior therapy for leukemia or myelodysplasia
- •AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
- •Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
研究组 & 干预措施
Placebo + chemotherapy
Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation
干预措施: Placebo (Drug)
Midostaurin + chemotherapy
Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.
干预措施: Midostaurin (Drug)
Midostaurin + chemotherapy
Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.
干预措施: Chemotherapy (Drug)
Placebo + chemotherapy
Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation
干预措施: Chemotherapy (Drug)
结局指标
主要结局
Event Free Survival (EFS)
时间窗: From date of Randomization up to approx. 30 months
EFS was defined as the time from randomization to failure to obtain a complete remission (CR) or Complete remission with incomplete hematologic recovery (CRi) with adequate blood count recovery in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurred first as assessed by the investigator.
次要结局
- Time to CR or CRi With Adequate Blood Count Recovery(At maximum 93 days from induction therapy start)
- Percentage of Participants With Minimal Residual Disease (MRD) Negative Status(from start of treatment up to end of post-consolidation (approximately 17 months))
- Disease-free Survival (DFS)(From date of CR or CRi with adequate blood count recovery up to approx. 30 months)
- AUClast: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8(0 - 12 hrs)
- Overall Survival (OS) (Key Secondary)(Between randomization to date of death up to approx. 30 months)
- Percentage of Participants With Minimal Residual Disease (MRD) Negative Status During Post-consolidation Phase(from start of post-consolidation to end of post-consolidation phase (up to 12 months))
- Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Hematological Recovery (CRi) But With Adequate Blood Count Recovery Rate.(At maximum 93 days from induction therapy start)
- Cumulative Incidence of Death (CID)(From date of CR or CRi with adequate blood count recovery up to approx. 30 months)
- Plasma Concentrations for Midostaurin and Its Metabolites: CGP52421 and CGP62221 for Non-poor Metabolizers(from Induction (IND) phase 0hr (predose) to Post-consolidation phase (POSTCONS) 12hr)
- Cmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8(0 - 12 hrs)
- Time to Measurable Residual Disease (MRD) Negativity by Flow Cytometry(From date of Randomization up to approx. 17 months)
- AUC0-t: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8(0 - 12 hrs)
- Cumulative Incidence of Relapse (CIR)(From date of CR or CRi with adequate blood count recovery up to approx. 30 months)
- Time to Partial and Full Neutrophil Recovery(At maximum 93 days from induction therapy start)
- Tmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8(0 - 12 hrs)
- Time to Partial and Full Platelet Recovery(At maximum 93 days from induction therapy start)
- Total Score for Each Time Point for the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)(From date of Randomization up to approx. 18 months)
- Scores for Each Time Point for the EQ5D-5L (a Visual Analogue Scale (VAS))(From date of Randomization up to approx. 18 months)