A PROSPECTIVE, RANDOMIZED, OPEN-LABEL PHASE 2 STUDY TO EVALUATE THE SUPERIORITY OF INOTUZUMAB OZOGAMICIN MONOTHERAPY VERSUS ALLR3 FOR INDUCTION TREATMENT OF CHILDHOOD HIGH-RISK OR VERY HIGH-RISK FIRST RELAPSE B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Pfizer
- 入组人数
- 100
- 试验地点
- 130
- 主要终点
- Minimum Residual Disease (MRD) Negativity in participants achieving complete response (CR), complete response with incomplete platelet count recovery (CRp), or complete response with incomplete count recovery (CRi)
研究概览
简要总结
This prospective, randomized, multicenter, open-label Phase 2 study is designed to evaluate the superiority of InO monotherapy vs ALLR3 after 1 cycle of induction treatment in paediatric participants (between 1 and <18 years) with High Risk (HR) or very high risk (VHR) first bone marrow relapse CD22-positive BCP ALL, and to evaluate the safety and tolerability, PK and long-term efficacy. Treatment with study intervention will end after induction therapy; follow-up will continue for up to 5 years from randomization.
详细描述
This prospective, randomized, multicenter, open-label, Phase 2 study is designed to evaluate the superiority of InO monotherapy vs ALLR3, after 1 cycle of induction treatment in paediatric participants (between 1 and <18 years) with HR or VHR first bone marrow relapse CD22-positive BCP ALL, and to evaluate the safety and tolerability, PK and long-term efficacy. Treatment with study intervention will end after induction therapy; follow-up for efficacy and safety will continue for up to 5 years from randomization.
End of Treatment is defined as occurring upon recovery from 1 cycle of study therapy (Day 28 ± 2 days), or one day before initiation of new anticancer therapy, whichever occurs first.
Approximately 100 participants will be randomized (2:1) to receive 1 cycle of either InO monotherapy or ALLR3 (block 1) therapy during induction. Two interim analyses (approximately 50% and 75% enrollment) fort the primary outcome measure followed by a final analysis are planned to assess efficacy and futility (non-binding).
After completion of induction therapy (ie, study therapy), it is anticipated that the majority of responding participants will proceed immediately to consolidation therapy. Non-responders are expected to proceed with salvage therapy at the investigator's discretion. Participants responding to induction therapy are expected to proceed to SOC consolidation therapy upon recovery of blood counts, but no sooner than 7 days after last dose of study intervention.
All participants (responders and non-responders) will proceed to long-term follow-up for this study. All subsequent anticancer therapy will be determined by the treating physician.
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
- None
入排标准
- 年龄范围
- 1 Year 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female participants between 1 and <18 years of age.
- •Morphologically confirmed diagnosis of first relapse HR or VHR BCP ALL; HR first relapse is defined as relapse occurring within 18 to 30 months of original diagnosis of ALL or within 6 months of completion of primary therapy, and lacking any identified very high-risk genetic abnormalities (Groeneveld-Krentz et al, 2019) (ie, KMT2A::AFF1 fusion [t(4;11)(q21;q23)], TCF3-HLF fusion [t(17;19)(q22;p13)], TCF3-PBX1 fusion [t(1;19)(q23;p13.3)], hypodiploidy [<40 chromosomes] or masked low hypodiploidy (Molina et al, 2021), TP53 alteration). VHR first relapse is defined as relapse within 18 months of original diagnosis of ALL and/or with any of the following genetic abnormalities at original diagnosis or at relapse (Groeneveld-Krentz et al, 2019) (ie, KMT2A::AFF1 fusion [t(4;11)(q21;q23)], TCF3-HLF fusion [t(17;19)(q22;p13)], TCF3-PBX1 fusion [t(1;19)(q23;p13.3)], hypodiploidy [<40 chromosomes] or masked low hypodiploidy (Molina et al, 2021), TP53 alteration).
- •CD22-positive ALL as defined by local institution;
- •Bone marrow involvement of ≥ 5% leukemic blasts (≥ M2 status).
- •Adequate serum chemistry parameters:
- •An eGFR in participants 1 to <2 years of age, or eCrCl in those 2 to <18 years of age, ≥30 mL/min using the recommended formula in Section 10.10.
- •AST and ALT ≤5 × institutional ULN at the time of randomization or pre-cytoreduction/general anesthesia; (Refer to Appendix 9 for France-specific requirement on the ALT/AST threshold);
- •Total bilirubin ≤1.5 × institutional ULN unless the participant has documented Gilbert's syndrome;
- •Prior history of thrombosis during corticosteroid use and/or asparaginase are eligible provided the patient receives anti-coagulant prophylaxis per institutional guidelines.
- •Cardiac shortening fraction ≥ 30% by echocardiogram or ejection fraction >50% by MUGA.
- •6 Participants with combined bone marrow and testicular relapse are eligible assuming orchiectomy is performed prior to randomization or is planned at the end of induction therapy.
排除标准
- •Any history of prior or ongoing hepatic SOS or prior liver failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)].
- •Prior allo-HSCT or CAR T-cell therapy.
- •Isolated extramedullary leukemia.
- •Philadelphia-chromosome positive ALL, ie. BCR-ABL/t(9;22) present.
- •Prior therapy with a calicheamicin-conjugated antibody (eg, InO or gemtuzumab ozogamicin).
- •Participants with active, uncontrolled bacterial, fungal, or viral infection.
- •Hypersensitivity/allergy to both PEG-ASP and Erwinia-ASP
研究组 & 干预措施
Inotuzumab ozogamicin
Each participant in the InO arm will receive 1 course (3 doses) of InO, as follows:
- Day 1: 0.8 mg/m2
- Days 8 (±1 day) and Day 15 (±1 day): 0.5 mg/m2/dose
干预措施: Inotuzumab ozogamicin (Drug)
ALLR3
Mitoxantrone 10 mg/m2 on Days 1 and 2 Vincristine 1.5 mg/m2 (max single dose 2 mg) administered on Days 3, 10, 17 and 24 Dexamethasone 20 mg/m2/day administered orally (or IV) divided into two daily doses (maximum 40 mg/day) as two 5-day blocks on Days 1-5 and Days 15-19.
PEG-asparaginase 1000 units/m2 IV administered on Days 3 and 17. In case of hypersensitivity/allergic reaction to PEG-asparaginase, each dose of PEG-asparaginase will be replaced by Erwinia-asparaginase at a dose of 20,000 units/m² IV or IM every other day for a total of 6 doses
干预措施: ALLR3 (Drug)
结局指标
主要结局
Minimum Residual Disease (MRD) Negativity in participants achieving complete response (CR), complete response with incomplete platelet count recovery (CRp), or complete response with incomplete count recovery (CRi)
时间窗: After 1 treatment cycle: Day 28 +/- 2 days
MRD negativity status is determined based on the minimum MRD percentage between the date of CR/CRp/CRi and end of treatment test as assessed by RQ-PCR, with reflex to FC result if MRD is non-evaluable by RQ-PCR
次要结局
- Rate of hematopoietic stem cell transplantation (HSCT)(Up to 5 years from randomization)
- Number of participants reporting an Adverse Event (AE)(From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.)
- Event Free Survival (EFS)(From study start to first event (progression, relapse, failure to achieve CR/CRp/CRi by the end of induction, MRD persistence prior to HSCT [hematopoietic stem cell transplant], second malignancy, or death): up to 5 years from randomization)
- Rate of Chimeric antigen receptor (CAR) T-cell therapy(Up to 5 years from randomisation)
- Duration of Response (DoR) for Participants Who Achieved CR/CRp/CRi(From date of first response to date of first event (objective progression, relapse as determined by investigator assessment, MRD persistence prior to HSCT, or death due to any cause, whichever occurs first): up to 5 years from End of Treatment)
- Pharmacokinetics (PK) parameter: InO Cmax(1 treatment cycle: 28 days)
- Number of Adverse Events (AE) reported by severity(From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.)
- Overall Survival (OS)(From start of treatment to date of death due to any cause: up to 5 years from randomization)
- Pharmacokinetics (PK) parameter: InO trough levels(1 treatment cycle: 28 days)