Phase 1B Open-Label, Dose-Escalation and Dose-Expansion Study of APVO436 in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndrome (MDS)
试验速览
- 阶段
- 1 期
- 入组人数
- 136
- 试验地点
- 24
- 主要终点
- Part 1 - Dose Escalation: Maximum Tolerated Dose
研究概览
简要总结
The primary objective of the Phase 1 part of the study is to determine the recommended dose of APVO436 administered intravenously to patients with AML or MDS. The primary objective of the Phase 1b part of the study is to evaluate the clinical activity of APVO436 in patients with AML or MDS.
APVO436 is being studied in this Phase 1b, open-label, multi-center, two-part dose-escalation/dose expansion study to evaluate the safety, pharmacokinetic/pharmacodynamic (PK/PD), and clinical activity of APVO436 in patients with AML and MDS. The study will be conducted in 2 parts. The first part of this Phase 1B study is an open-label, multiple dose ascending dose escalation phase to determine the recommended dose (RP2D) level of APVO436 for future Phase 2 studies. The goal of the dose expansion phase of the study (Part 2) is to (i) evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care and (ii) obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities.
Study Objectives for Dose Escalation Phase
- Primary Objectives are to:
- Determine the RP2D level of APVO436 administered intravenously (IV) in patients with AML or MDS, and
- Evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care and obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities.
- Secondary Objectives are to:
- Define the safety profile and immunogenicity of APVO436; to determine the PK/PD of APVO436; to evaluate the clinical activity of APVO436 in AML and MDS patients.
- Further evaluate the safety profile and immunogenicity of APVO436 and the PK/PD of APVO436 and the relationship between PK/PD and clinical response.
Study Objectives for Dose Expansion Phase
- Primary Objective is to evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care.
- Secondary Objective is to obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities.
详细描述
Part 1 - Dose Escalation:
Dosing will start at the minimum anticipated biologic effect level (MABEL) in single-patient cohorts for the first 3 dose cohorts up to and including 3 mcg. Patients enrolled will have either: 1) relapsed or refractory AML and refuse or are not eligible for intensive chemotherapy or an allogeneic stem cell transplant, or 2) relapsed or refractory MDS and have > 5% blasts in the marrow or any circulating blasts in the peripheral blood and have failed a prior hypomethylating agent (HMA); failure is defined as intolerance to HMA, lack of response (no CR by at least 6 cycles), or have IWG defined progressive disease during or after treatment with an HMA.
In single-patient Cohorts 1 to 3, the next dose cohort will only enroll after the patient in the current dose cohort has completed the first cycle of dosing (4 weeks) and no Grade ≥ 2 adverse events (AEs) (hematologic or non-hematologic) have occurred. If any Grade ≥ 2 AE occurs in the single-patient cohorts, then that cohort and all subsequent single-patient cohorts will be expanded to a 3 + 3.
The next dose cohort in the 3 + 3 cohorts (all cohorts beyond Cohort 4) is started after patients in the previous dose cohort have completed the first cycle of dosing and an evaluation of AEs for DLTs during the DLT observation period has been completed. For the first 2 patients within each dose cohort, administration of the first dose must be separated by a minimum of 36 hours. At the conclusion of each cycle, patients with significant cytopenias without evidence of leukemia will have the dose delayed.
Beginning in Cohort 5, and for all cohorts going forward, stepped dosing will be introduced to mitigate against the development of infusion-related reactions and cytokine release syndrome.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Part 1 - Dose Escalation: Maximum Tolerated Dose
时间窗: during first 28 to 35 days of treatment
Identify the maximum tolerated dose in dose-escalation (Phase 1) by assessment of dose-limiting toxicities
Part 2 - Dose Expansion: Safety
时间窗: during first 28 to 35 days of treatment
The cumulative incidence of Grade 3-4 AEs, and SAEs, and the incidence of AES of interest (≥Grade 2 CRS, ≥Grade 2 Infusion related reaction, ≥2 cardiac toxicity and ≥2 neurotoxicity as complications of CRS) for safety
次要结局
- Part 1 - Dose Escalation: Changes in peripheral blasts to measure pharmacodynamics of APVO436(Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.)
- Part 1 - Dose Escalation: Immunogenicity of APVO436(Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.)
- Part 2 - Dose Expansion: Efficacy - Incidence of composite CR (CR + CRi + CRh)(Patient will have assessment at the end of each Cycle (each Cycle is 28 days) up to 2 years)
- Part 2 - Dose Expansion: Efficacy - MRD Status(Patient will have assessment through study completion, an average of 1 year)
- Part 1 - Dose Escalation: Frequency and severity of adverse events as assessed by CTCAE v5.0(Patient will be followed for the duration of treatment, an expected average of 6 months, and for up to 7 days following last treatment)
- Part 1 - Dose Escalation: Maximum serum drug concentration(Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.)
- Part 1 - Dose Escalation: Area under the concentration-time curve (AUC)(Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.)
- Part 1 - Dose Escalation: Elimination of half-life(Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.)
- Part 1 - Dose Escalation: Changes in T-cell populations to measure pharmacodynamics of APVO436(Patient will have laboratory assessments prior to dosing on Day 1, throughout the study, and up to 7 days following last dose.)
- Part 2 - Dose Expansion: Exploratory - 2-year LFS rate(2 years)
- Part 2 - Dose Expansion: Exploratory - MRD(1 month and 4 months)
- Part 2 - Dose Expansion: Exploratory - LFS(Up to 2 years)
- Part 2 - Dose Expansion: Exploratory - 1-year LFS rate(1 year)