2023-510009-16-00
招募中
1/2 期
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
概览
- 阶段
- 1/2 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 12
- 主要终点
- Efficacy (ie, the primary outcome measure): CRc rate after completion of up to 2 Re-Induction Cycles.(based on investigator’s assessment).
概览
简要总结
Phase 1 only:
- To determine the recommended Phase 2 dose (RP2D) of quizartinib, in combination with chemotherapy, for subjects in the older (≥1 year to ≤ 21 years) and younger (≥1 month to <12 months) age groups.
- To determine the composite complete remission (CRc) rate (ie, complete remission [CR] + CR with incomplete recovery [CRi]) after completion of up to 2 Re-Induction Cycles.
- To determine the safety and cumulative toxicity of quizartinib administered in combination with re-induction chemotherapy for up to 2 cycles, with optional consolidation therapy, and as a single-agent continuation therapy over ≤12 cycles.
- To determine estimates of individual pharmacokinetic (PK) parameters of quizartinib and AC886 (metabolite of quizartinib).
入排标准
- 年龄范围
- 0 years 至 64 years（18-64 Years, 0-17 Years）
- 接受健康志愿者
- 是
入选标准
- •Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with ≥5% blasts in bone marrow, with or without extramedullary disease
- •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
- •Female subjects must not donate or retrieve for their own use ova from the time of Screening and throughout the treatment period, and for at least 7 months following the last dose
- •Male subjects must not freeze or donate sperm starting at Screening and throughout the treatment period, and at least 4 months following the last dose.
- •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 previous anti-cancer therapy prior to Re-Induction Cycle 1, Day 1, defined as toxicities (other than alopecia) not yet resolved by the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) to Grade ≤ 1 or baseline.
排除标准
- •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
- •Is otherwise considered inappropriate for the study by the Investigator
- •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)
结局指标
主要结局
Efficacy (ie, the primary outcome measure): CRc rate after completion of up to 2 Re-Induction Cycles.(based on investigator’s assessment).
Efficacy (ie, the primary outcome measure): CRc rate after completion of up to 2 Re-Induction Cycles.(based on investigator’s assessment).
Safety: The safety profile of quizartinib administered in combination with reinduction chemotherapy for up to 2 cycles, with optional consolidation chemotherapy, and as a single-agent continuation therapy over ≤12 cycles. And phase 1 only: Number of DLTs in dose cohorts in Re-Induction Cycle 1
Safety: The safety profile of quizartinib administered in combination with reinduction chemotherapy for up to 2 cycles, with optional consolidation chemotherapy, and as a single-agent continuation therapy over ≤12 cycles. And phase 1 only: Number of DLTs in dose cohorts in Re-Induction Cycle 1
Estimates of AUC, apparent clearance (CL/F), and apparent volume of distribution (Vz/F) for quizartinib and AC886 by the use of PopPK modeling or other applicable methods
Estimates of AUC, apparent clearance (CL/F), and apparent volume of distribution (Vz/F) for quizartinib and AC886 by the use of PopPK modeling or other applicable methods
次要结局
- CR rate after completion of Re-Induction Cycle 1 which is defined as the percent of subjects achieving CR after completion of Re-Induction Cycle 1
- CRi rate after completion of Re-Induction Cycle 1, which is defined as the percent of subjects achieving a CRi after completion of Re-Induction Cycle 1
- CRc rate after completion of Re-Induction Cycle 1, which is defined as the percent of subjects achieving CR+ CRi after completion of Re- Induction Cycle 1
- Time to relapse, defined as the time from the first documented response (CR, CRi) until documented relapse
- Rate of relapse after 1, 2 and 3 years
- Cumulative incidence of relapse at the end of the study, defined as the percentage of subjects who achieved CRc at the end of Re-Induction and relapse at these defined time points
- OS, defined as the time from the start of Re-Induction therapy until death from any cause
- EFS defined as the time from the start of Re-Induction therapy until the earliest date of the following: - Refractory disease (or treatmetn failure) at the end of Re-Induction. - Relapse after CR or CRi. - Death from any cause at any time during the study.
- Pharmacodynamic: Inhibition of FLT3-ITD autophosphorylation activity in an ex-vivo PIA during Re-Induction, Continuation, and at the time of relapse
- FLT3-ITD to FLT3-WT allelic ratio at Screening, during Re- Induction, and at the time of relapse
- Mutations present in blasts (eg, in the kinase and juxtamembrane domains of FLT3 and other mutations known to be associated with AML) at Screening and at the time of refractory disease or relapse
- Biomarker: Rate of CRc (CR, CRi) without MRD using next generation sequencing
- Others: Acceptability including palatability of quizartinib formulations
- Efficacy (ie, the secondary outcome measures): CR rate, which is defined as the percent of subjects achieving a CR after completion of up to 2 Re-Induction cycles
- CRi rate, which is defined as the percent of subjects achieving CRi after completion of up to 2 Re-Induction Cycles.
- Duration of CR defined as the time from the first documented CR until documented relapse
- Duration of CRi, defined as the time from the first documented CRi until documented relapse
- Duration of CRc, defined as the time from the first documented CR or CRi until documented relapse
研究者
Clinical Trial Office
Scientific
Daiichi Sankyo Inc.
研究点 (12)
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