A Phase 1/2 Open-label Study to Investigate the Safety, Efficacy, and Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the Treatment of Adults and Adolescents With Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL) and Minimal Residual Disease Positive (MRD+) B-ALL
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Amgen
- 入组人数
- 181
- 试验地点
- 154
- 主要终点
- Dose Escalation Phase: Number of participants who experience dose limiting toxicities (DLTs)
研究概览
简要总结
The Phase I part of the study aims to evaluate the safety, efficacy, and tolerability of subcutaneous (SC) blinatumomab for treatment of Relapsed or Refractory B cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL), to determine the maximum tolerated dose (MTD), and recommended phase 2 dose(s) (RP2D) of SC administered blinatumomab.
The Phase II part of the study will evaluate the safety, efficacy, and tolerability of SC blinatumomab for treatment of R/R B-ALL and Minimum Residual Disease Positive (MRD+) B-ALL in participants 12 years old and greater. It will also conduct a clinical pharmacokinetic (PK) evaluation of SC1 and SC2 blinatumomab formulations.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ph-IIC, Dose Escalation and Dose Expansion: Aged 18 years or older (or same or greater than legal age within the country if it is older than 18 years).
- •Ph-IIRa and Ph-IIMa: Aged ≥ 17 years at time of informed consent.
- •Ph-IIRb and Ph-IIMb: Age ≥ 12 years and < 17 years at time of informed consent.
- •Ph-IIR, Ph-IIC, Dose escalation, Dose Expansion: Participants with R/R B-precursor ALL.
- •Relapsed or Refractory B-precursor ALL at any time after first salvage therapy.
- •Relapsed B-precursor ALL at any time after allogenic hematopoietic stem cell transplant (HSCT).
- •Ph-IIR, Ph-IIC, Dose escalation, Dose expansion: Greater than or equal to 5% blasts in the Bone Marrow per local assessment.
- •Ph-IIM: B-precursor ALL and bone marrow blasts (BMB) ≥ 0.01% and < 5% per local assessment.
- •Ph-IIM: Availability of an appropriate archival BM specimen from initial or relapse diagnosis and the screening BM sample.
- •Participants aged ≥ 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to
- •Participants aged 16 to < 18 years old: Karnofsky Performance Score ≥ 50%.
- •Participants aged < 16 years old: Lansky Performance Score ≥ 50%.
- •Any Ph+ participant intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are eligible.
- •Ph-IIM: BM function as follows:
- •Absolute Neutrophil Count (ANC) ≥ 500/μL
- •Platelet count ≥ 50 000/μL (transfusion permitted)
- •Hemoglobin level ≥ 9 g/dL (transfusion permitted)
- •The above is a summary, other inclusion criteria details may apply.
排除标准
- •Active ALL in the central nervous system (CNS). Presence of greater than 5 white blood cells per cubic millimeter in cerebrospinal fluid (CSF) with lymphoblasts present and/or clinical signs of CNS leukemia. If CSF leukemia is present subjects will have to receive intrathecal therapy and have documented negative CSF prior to enrolling.
- •History or presence of clinically relevant CNS pathology (excluding headache) such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis or severe (≥ grade 3) CNS events including immune effector cell-associated neurotoxicity syndrome (ICANS) from prior chimeric antigen receptor T-cell (CAR T) or other T cell engager therapies.
- •Isolated Extramedullary (EM) Disease.
- •For Ph-IIM only: Current EM disease or presence of circulating leukemia blasts.
- •Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
- •Active acute or chronic graft versus host disease requiring systemic treatment with immunosuppressive medication.
- •Symptoms and/or signs that indicate an acute or uncontrolled chronic infection, any other disease or condition that could be exacerbated by the treatment or would complicate protocol compliance.
- •Testicular leukemia.
- •History of malignancy (with certain exceptions) other than ALL within 3 years prior to start of protocol-specified therapy.
- •Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy.
- •Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy (with certain exceptions).
- •Immunotherapy within 4 weeks before start of protocol-specified therapy.
- •Prior failed cluster of differentiation (CD19) directed therapy such as prior blinatumomab or CD19 CAR T cells will be allowed (with demonstrated continued CD19+ expression), if treatment ended more than 4 weeks prior to start of protocol therapy and no prior CNS complications.
- •Currently receiving treatment in or less than 30 days or 5 half-lives since ending treatment on another investigational study(ies).
- •Abnormal screening laboratory parameters.
- •Female participant: Pregnant or breastfeeding or planning to become pregnant or donate eggs, or expected to breastfeed during treatment and for 96 hours after the last dose of investigational product (SC blinatumomab).
- •The above is a summary, other exclusion criteria details may apply.
研究组 & 干预措施
Dose Escalation Phase: Blinatumomab Subcutaneous Formulation 1 (SC1)
Cohorts of at least 3 adult participants with R/R B-ALL will be treated with escalating doses of blinatumomab to determine the maximum tolerated dose (MTD). The MTD will be defined as the dose for which the estimate of the toxicity rate from an isotonic regression (Yan et al, 2017) is closest to the target toxicity rate. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy will be assessed.
干预措施: Blinatumomab (Drug)
Dose Expansion Phase: Blinatumomab SC1
Up to 4 cohorts of adult participants with R/R B-ALL will be enrolled at different dose levels to support identification of the RP2D. Each cohort will aim to further assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy.
干预措施: Blinatumomab (Drug)
Ph-IIM: Efficacy of SC Blinatumomab in Participants with MRD+ B-ALL
The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with MRD+ B-ALL.
干预措施: Blinatumomab (Drug)
Ph-IIR: Efficacy of SC Blinatumomab in Participants with R/R B-ALL
The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with R/R B-ALL.
干预措施: Blinatumomab (Drug)
Ph-IIC: Clinical PK Evaluation of SC Blinatumomab Formulations
1 cohort of adult participants will be enrolled into the Ph-IIC arm. The clinical PK evaluation cohort (Ph-IIC) will be conducted to compare the PK of SC1 and SC2 formulations at the preliminary RP2D determined from the dose expansion phase, in participants with R/R B-ALL.
干预措施: Blinatumomab (Drug)
结局指标
主要结局
Dose Escalation Phase: Number of participants who experience dose limiting toxicities (DLTs)
时间窗: Up to 29 days
Dose Escalation Phase: Number of participants who experience one or more treatment-emergent adverse events (TEAEs)
时间窗: Up to approximately 28 weeks
Dose Escalation Phase: Number of participants who experience one or more serious TEAEs
时间窗: Up to approximately 28 weeks
Dose Escalation Phase: Number of participants who experience one or more adverse events (AEs) of Interest (AEIs)
时间窗: Up to approximately 28 weeks
Dose Escalation Phase: Number of participants who experience dose limiting toxicities (DLTs)
时间窗: Up to 29 days
Dose Escalation Phase: Number of participants who experience one or more treatment-emergent adverse events (TEAEs)
时间窗: Up to approximately 28 weeks
Dose Expansion and Phase 2 Ph-IIR cohort: Number of participants who achieve complete remission (CR) / complete remission with partial hematological recovery (CRh)
时间窗: Up to 10 weeks
Dose Escalation Phase: Number of participants who experience one or more serious TEAEs
时间窗: Up to approximately 28 weeks
Dose Escalation Phase: Number of participants who experience one or more treatment-related TEAEs
时间窗: Up to approximately 28 weeks
Dose Escalation Phase: Number of participants who experience one or more adverse events (AEs) of Interest (AEIs)
时间窗: Up to approximately 28 weeks
Phase 2 Ph-IIC cohort: Maximum concentration (Cmax) of blinatumomab SC1 and SC2
时间窗: Up to approximately 4 weeks
Phase 2 Ph-IIC cohort: Average concentration (Cavg) of blinatumomab SC1 and SC2
时间窗: Up to approximately 4 weeks
Phase 2 Ph-IIC cohort: Time to reach maximum concentration (Tmax) of blinatumomab SC1 and SC2
时间窗: Up to approximately 4 weeks
Phase 2 Ph-IIC cohort: Area under the concentration-time curve (AUC) of blinatumomab SC1 and SC2
时间窗: Up to approximately 4 weeks
Phase 2 Ph-IIM cohort: Number of participants who achieve CR with MRD-negative response
时间窗: Up to 10 weeks
次要结局
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Summary scores of quality of life at each assessment as assessed by the EORTC QLQ-C30 for participants aged ≥ 17 years at the time of consent(Baseline (Day 1) up to approximately 28 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Summary scores of quality of life at each assessment as assessed by PedsQL Generic Core Scale for participants aged 12 to < 17 years at time of consent(Baseline (Day 1) up to approximately 28 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Change from baseline of quality of life as assessed by PedsQL Generic Core Scale for participants aged 12 to < 17 years at time of consent(Baseline (Day 1) up to approximately 28 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Blinatumomab serum concentrations for participants not participating in intense PK sampling assessment(Up to approximately 4 weeks)
- Dose Escalation and Dose Expansion Phase: Minimum concentration over the dosing interval (Cmin) of blinatumomab(Up to approximately 10 weeks)
- Dose Escalation and Dose Expansion Phase: Cmax of blinatumomab(Up to approximately 10 weeks)
- Dose Escalation and Dose Expansion Phase: Tmax of blinatumomab(Up to approximately 10 weeks)
- Dose Escalation and Dose Expansion Phase: AUC of blinatumomab(Up to approximately 10 weeks)
- Dose Escalation Phase and Phase 2 (Ph-IIC cohort): Number of participants who achieve CR/CRh(Up to 10 weeks)
- Dose Escalation Phase, Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants with incidence of anti-blinatumomab antibody formation(Up to approximately 28 weeks)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Overall survival (OS)(Up to approximately 2 years)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort and Ph-IIC cohort): Duration of response(Up to approximately 2 years)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Relapse free survival(Up to approximately 2 years)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more TEAEs(Up to approximately 28 weeks)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more serious treatment-emergent adverse event(Up to approximately 2 years)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more treatment-related treatment-emergent adverse events(Up to approximately 28 weeks)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more AEIs(Up to approximately 28 weeks)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Summary scores of quality of life at each assessment as assessed by the EORTC QLQ-C30 for participants aged ≥ 17 years at the time of consent(Baseline (Day 1) up to approximately 28 weeks)
- Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Change from baseline of quality of life as assessed by the EORTC QLQ-C30 for participants aged ≥ 17 years at the time of consent(Baseline (Day 1) up to approximately 28 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Summary scores of quality of life at each assessment as assessed by PedsQL Generic Core Scale for participants aged 12 to < 17 years at time of consent(Baseline (Day 1) up to approximately 28 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Change from baseline of quality of life as assessed by PedsQL Generic Core Scale for participants aged 12 to < 17 years at time of consent(Baseline (Day 1) up to approximately 28 weeks)
- Phase 2 (Ph-IIR cohort): Number of participants who achieve CR(Up to 10 weeks)
- Phase 2 (Ph-IIR cohort): Number of participants who achieve CR, CRh, CRi (complete remission with incomplete hematological recovery) or blast free hypoplastic or aplastic bone marrow (BM)(Up to 10 weeks)
- Phase 2 (Ph-IIM cohort): Number of participants who achieve CR, CRh, CRi or blast free hypoplastic or aplastic BM with MRD-negative response(Up to 10 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Number of participants who achieve CR or CRh with MRD-negative response(Up to 10 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Duration of molecular response(Up to approximately 2 years)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Cmax of blinatumomab for participants participating in intense PK sampling assessment(Up to approximately 4 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Tmax of blinatumomab for participants participating in intense PK sampling assessment(Up to approximately 4 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): AUC of blinatumomab for participants participating in intense PK sampling assessment(Up to approximately 4 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Blinatumomab serum concentrations for participants not participating in intense PK sampling assessment(Up to approximately 4 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Proportion of time on treatment with high side effect bother from baseline to end of treatment as measured by Functional Assessment of Chronic Illness Therapy (FACIT) GP5 item for participants aged ≥ 17 years(Baseline (Day 1) up to approximately 28 weeks)
- Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Pain difference between pain score before and after injection as reported using the Numeric Rating Scale (NRS-11) for participants aged 12 to < 17 years at time of consent(Up to approximately 28 weeks)