A Phase 1/2, Multicenter, Dose-Escalating Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy Of Quizartinib Administered in Combination With Re-Induction Chemotherapy, and as a Single-Agent Continuation Therapy, in Pediatric Relapsed/Refractory AML Subjects Aged 1 Month to <18 Years (and Young Adults Aged up to 21 Years) With FLT3-ITD Mutations
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 65
- 试验地点
- 27
- 主要终点
- Pharmacokinetic parameter apparent volume of distribution (Vz/F) for quizartinib and AC886 (Phase 1 and 2)
研究概览
简要总结
Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research.
Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission or is not responding to treatment.
详细描述
The medical condition being investigated is relapsed or refractory AML in participants aged ≥1 month to ≤21 years with Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations (FLT3-ITD AML), following failure of front-line intensive chemotherapy.
The trial will be conducted in multiple phases. An independent data monitoring committee (DMC) will protect the rights, safety, and well-being of participants by monitoring the progress and results. The DMC will comprise qualified physicians and scientists who are not Investigators in the study and not otherwise directly associated with the Sponsor and will be convened at the end of Phase 1.
A. Dose Escalation/De-escalation Phase:
Number of participants is determined by age group. Participants will be enrolled by dose-level to determine the recommended Phase 2 dose (RP2D) of quizartinib for pediatric participants that provides similar exposure to adult patients treated at the target adult dose of 60 mg orally once daily.
B. Dose-Expansion Phase:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Month 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria to be eligible for enrollment into the study:
- •Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with ≥5% blasts in bone marrow, with or without extramedullary disease
- •In first relapse or refractory to first-line high-dose chemotherapy with no more than 1 attempt (1 to 2 cycles of induction chemotherapy) at remission induction - prior HSCT is permitted
- •Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as defined in the protocol
- •Is between 1 month and 21 years of age at the time the Informed Consent/Assent form is signed
- •Has protocol-defined adequate performance status score
- •Has fully recovered from the acute clinically significant toxicity effects of all prior chemotherapy, immunotherapy, or radiotherapy, per protocol guidelines
- •Has protocol-defined adequate renal, hepatic and cardiac functions
- •If of reproductive potential, is permanently sterile or agrees to use highly effective birth control upon enrollment, during the period of therapy, and for 6 months following the last dose of quizartinib, etoposide, fludarabine, methotrexate, or cytarabine, whichever is later
- •If female of child-bearing potential, tests negative for pregnancy and agrees not to breast feed
- •Male participants must be surgically sterile or willing to use highly effective birth control during the treatment period, and for 6 months following the last dose of quizartinib, etoposide, fludarabine, methotrexate, or cytarabine, whichever is later.
- •Participant/legal representative is capable of understanding the investigational nature of the study, potential risks, and benefits, and the patient (and/or legal representative) signs a written assent/informed consent
排除标准
- •Participants who meet any of the following criteria will be disqualified from entering the study:
- •Has been diagnosed with isolated central nervous system relapse, acute promyelocytic leukemia (APL), juvenile myelomonocytic leukemia, French-American-British classification M3 or WHO classification of APL with translocation, or with myeloid proliferations related to Down syndrome
- •Has uncontrolled or pre-defined significant cardiovascular disease as detailed in the protocol
- •Has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient must be off vasopressors and have negative blood cultures for at least 48 hours prior to the start of systematic protocol therapy.
- •Has known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
- •Has known history of human immunodeficiency virus (HIV)
- •Has history of hypersensitivity to any of the study medications or their excipients
- •Is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol
- •Has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance, interfere with consent/assent, study participation, follow up, or interpretation of study results
- •Is currently participating in another investigative interventional procedure (observational or long-term interventional follow-up is allowed)
- •Is otherwise considered inappropriate for the study by the Investigator
研究组 & 干预措施
All Participants
All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.
干预措施: Quizartinib (Drug)
All Participants
All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.
干预措施: Fludarabine (Drug)
All Participants
All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.
干预措施: Cytarabine (Drug)
All Participants
All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.
干预措施: Intrathecal (IT) triple chemotherapy prophylaxis (Drug)
All Participants
All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.
干预措施: Etoposide (Drug)
结局指标
主要结局
Pharmacokinetic parameter apparent volume of distribution (Vz/F) for quizartinib and AC886 (Phase 1 and 2)
时间窗: Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days)
Composite complete remission (CRc) rate among participants with acute myeloid leukemia (AML) (Phase 1 and 2)
时间窗: within 8 years, 8 months
CRc rate is defined as percentage of participants with best response of complete remission (CR) or CR with incomplete hematological recovery (CRi) after completion of up to 2 re-induction cycles
Pharmacokinetic parameter area under the concentration curve for quizartinib and AC886 (Phase 1 and 2)
时间窗: Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days)
Pharmacokinetic parameter apparent clearance (CL/F) for quizartinib and AC886 (Phase 1 and 2)
时间窗: Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days)
Number of dose-limiting toxicities (Phase 1)
时间窗: Re-induction Cycle 1 Day 1 up to Day 28 (each cycle is 28 days)
次要结局
- Complete remission (CR) rate among participants with AML (Phase 1 and 2)(on Day 56 (± 3 Days) for the last subject, within 4 years)
- Complete remission with incomplete recovery (CRi) rate among participants with AML (Phase 1 and 2)(on Day 56 (± 3 Days) for the last subject, within 4 years)
- Duration of CR among participants with AML (Phase 1 and 2)(within 8 years, 8 months)
- Cumulative incidence of relapse among participants with AML at the end of study (Phase 1 and 2)(within 8 years, 8 months)
- Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2)(on Day 56 (± 3 Days) for the last subject, within 4 years)
- Time to relapse among participants with AML (Phase 1 and 2)(within 8 years, 8 months)
- Duration of CRi among participants with AML (Phase 1 and 2)(within 8 years, 8 months)
- Duration of composite complete remission (CRc) among participants with AML (Phase 1 and 2)(within 8 years, 8 months)
- Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2)(on Day 56 (± 3 Days) for the last subject, within 4 years)
- Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2)(on Day 56 (± 3 Days) for the last subject, within 4 years)
- Rate of relapse among participants with AML after 1, 2 and 3 years (Phase 1 and 2)(within 8 years, 8 months)
- Overall survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2)(within 8 years, 8 months)
- Event-free survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2)(within 8 years, 8 months)
- Number of participants proceeding to high-dose conditioning therapy/allogeneic hematopoietic stem cell transplantation (HSCT) (including transplant-related mortality) among participants with AML (Phase 1 and 2)(within 8 years, 8 months)
- Rate of CRc (CR or CRi) without minimal residual disease (MRD) using next generation sequencing among participants with AML (Phase 1 and 2)(within 8 years, 8 months)
- Acceptability of including the palatability of quizartinib formulations among participants with AML (Phase 1 and 2)(within 8 years, 8 months)