Open-label, Phase I/II Study to Evaluate Safety and Efficacy of Asciminib With Chemotherapy Followed by Asciminib Plus Blinatumomab in Pediatric, Adolescent, and Young Adults With Relapsed or Refractory BCR::ABL1-positive (Philadelphia Positive, Ph+) or BCR::ABL1-like (Ph-like) ALL
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 3
- 主要终点
- Part 1 Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) occurring during cycle 1 (debulking induction)
研究概览
简要总结
Multi-center, open-label, single arm study of asciminib in participants aged ≥1 year to ≤30 years old with r/r Ph+ or ABL-class Ph-like ALL. This study will have 2 parts: Part 1 dose escalation and Part 2 dose expansion. Part 1 dose escalation will enroll participants aged ≥1 year to ≤30 years to determine the recommended phase 2 dose (RP2D) of asciminib when administered with low intensity chemotherapy. Part 2 dose expansion will enroll participants aged ≥1 year to ≤30 years to evaluate safety, tolerability, and efficacy of asciminib at the RP2D with the treatment regimen.
详细描述
This is a single arm phase I/II multicenter study to assess the safety and efficacy of asciminib at the RP2D in combination with low intensity chemotherapy (debulking induction) followed by asciminib plus blinatumomab (consolidation) in pediatric and young adult participants with r/r Ph+ ALL (inclusive of participants with T315I mutation).
The aim of the study design is to explore a novel treatment regimen which is expected to be more tolerable than the high intensity chemotherapy backbone-based regimens.
This study will consist of a 2-part design:
Part 1 dose escalation using a Bayesian Optimal Interval (BOIN) statistical design, and after determination of RP2D Part 2 dose expansion.
Participants will only enroll in either Part 1 or Part 2, and not both.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Evidence of Ph+ ALL or ABL1 or ABL2 fusion Ph-like ALL, inclusive of participants with ABL1 T315I mutation
- •Participants with CNS1, CNS2, CNS3a, or CNS3b at screening
- •Active B-Cell ALL at screening defined by MFC or IG/TCR PCR of ALL blasts >0.01% in participants with either:
- •Primary refractory disease (>0.01% ALL blasts present at the end of consolidation) OR
- •Relapsed ALL with evidence of involvement of BM with ALL (MFC or IG/TCR PCR >0.01%) after at least one line of therapy
- •Documented history of CD19 expressing B-cell ALL (in peripheral blood or bone marrow by flow cytometry).
- •a) For participants who received anti-CD19 targeted therapy (e.g CD19 CAR T cells or blinatumomab), CD19 expressing B-cell ALL must be documented after anti-CD19 therapy completion prior to cycle 1 day 1
- •Adequate hepatic and renal function (local laboratory analysis) as defined:
- •ALT ≤ 5x upper limit of normal (ULN) for age
- •Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x ULN) for age, except for participants with Gilbert's syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
- •Estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula in participants ≥ 18 years, OR radioisotope GFR ≥50 mL/min/1.73 m^2, OR creatinine based on age and sex for participants < 18 years old
- •Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) OR left ventricular ejection fraction of ≥50% by ECHO
排除标准
- •Participants with >3 relapses of ALL
- •Extramedullary disease (non-CNS and/or isolated CNS disease)
- •Participants with CNS3c (Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome))
- •Cardiac or cardiac repolarization abnormality, including but not limited to clinically significant cardiac arrhythmias, long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or other clinically significant heart disease (e.g., congestive heart failure, etc.)
- •Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol.
- •Other protocol defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Methotrexate (intrathecal) (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Dexamethasone (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Blinatumomab (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Cytarabine (intrathecal) (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Hydrocortisone (intrathecal) (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Vincristine (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Asciminib Adult formulation (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Asciminib Pediatric formulation (Drug)
Single Arm
Asciminib Adult formulation group: escalating doses evaluated
Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose.
For known T315I mutation:
Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily.
干预措施: Prednisolone (intrathecal) (Drug)
结局指标
主要结局
Part 1 Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) occurring during cycle 1 (debulking induction)
时间窗: During Cycle 1 (Cycle 1 = 28 days)
A dose-limiting toxicity (DLT) is defined as an adverse event which starts between Day 1 and Day 28, is suspected by the investigator to be related to asciminib, and meets one of the several criteria.
Part 1 Dose Escalation: Incidence and severity of adverse events (AEs) during cycle 1 (debulking induction)
时间窗: During Cycle 1 (Cycle = 28 days)
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Part 2 Dose Expansion: Percentage of complete response/remission (CR) evaluable participants who achieve CR treated at recommended phase 2 dose (RP2D) (debulking induction)
时间窗: End of Cycle 1 (Cycle 1 = 28 days)
Participants with Complete Response/Remission (CR) will achieve the following: No circulating blasts or extramedullary disease; No lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass/CNS involvement; Marrow \<5% blasts (M1) OR \< 1% blasts by flow cytometry. If a discrepancy occurs between disease detection methods, the result of the flow cytometry assay will be used to determine CR status; Peripheral blood count recovery; ANC \> 1000μL and platelets \> 100,000μL. CR evaluable: Participants will be considered CR evaluable for Part 2 if they have relapsed/refractory Ph+ ALL defined as either \>1% bone marrow (BM) blasts by MFC or immunoglobulin/T-cell receptor (IG/TCR) PCR, OR \> 5% BM blasts by morphologic evaluation at enrollment and are treated at RP2D.
Part 1 Dose Escalation: To determine the Recommended Phase II Dose (RP2D) of asciminib when administered with low intensity chemotherapy
时间窗: During Cycle 1 (Cycle 1 = 28 days)
An integrated assessment of tolerability, safety profiles, dose-limiting toxicities (DLTs), treatment responses, and available pharmacokinetic (PK) data.
Part 2 Dose Expansion: Assess the rate of complete remission (CR) at RP2D
时间窗: End of Cycle 1 (Cycle 1 = 28 days)
Percentage of participants achieving complete remission (CR)
次要结局
- Complete remission (CR) rate(End of Cycle 2 and Cycle 3 (Cycle 2 & 3 = 42 days))
- Next generation sequencing (NGS) minimal residual disease (MRD) negative rate(At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days))
- Multiparametric flow cytometry (MFC) MRD negative CR rate(At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days))
- Overall MRD negative response (MRD negative CR and/or CRi rate) by NGS(at and by the end of cycle 1 (debulking induction) (Cycle 1 = 28 days), cycle 2, and cycle 3 (consolidation) (each cycle = 42 days))
- Overall MRD negative response (MRD negative CR and/or CRi rate) by MFC(at and by the end of cycle 1 (Cycle 1 = 28 days) (debulking induction), cycle 2, cycle 3 (consolidation) (each cycle = 42 days))
- Overall response rate (ORR)(At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days))
- Multiparametric flow cytometry (MFC) MRD negative CR/CRi rate(At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days))
- Disease Free Survival (DFS)(End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years))
- Overall survival (OS)(End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years))
- Pharmacokinetic (PK) parameter of asciminib at steady state: AUClast(Cycle 1, Day 8 (Cycle 1 = 28 days))
- PK parameter of asciminib at steady state: Cmax(Cycle 1, Day 8 (Cycle 1 = 28 days))
- PK parameter of asciminib at steady state: Tmax(Cycle 1, Day 8 (Cycle 1 = 28 days))
- PK parameter of asciminib at steady state: Ctrough(Cycle 1, Day 8 (Cycle 1 = 28 days); Cycle 2, Day 22 (Cycle 2 = 42 days); Cycle 3, Day 22 (Cycle 3 = 42 days))