A First-In-Human, Open-Label, Multicenter Study of VOR33 in Patients With Acute Myeloid Leukemia Who Are at High-Risk for Leukemia Relapse Following Hematopoietic Cell Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 67
- 试验地点
- 15
- 主要终点
- Incidence of neutrophil engraftment
研究概览
简要总结
This is a Phase 1/2a, multicenter, open-label, first-in-human (FIH) study of VOR33 in participants with AML or MDS who are undergoing human leukocyte antigen (HLA)-matched allogeneic hematopoietic cell transplant (HCT).
详细描述
High risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) frequently relapses despite hematopoietic stem cell transplant (HCT). Post-HCT targeted therapy to reduce relapse is limited by toxicity to the engrafted cells. VOR33, an allogeneic CRISPR/Cas9 genome-edited hematopoietic stem and progenitor cell (HSPC) therapy product, lacking the CD33 protein, is being investigated for participants with CD33+ AML or MDS at high risk for relapse after HCT to allow post-HCT targeting of residual CD33+ acute AML cells using Mylotarg™ without toxicity to engrafted VOR33 cells. Participants will undergo a myeloablative HCT with matched related or unrelated donor CD34+-selected hematopoietic stem and progenitor cells (HSPCs) engineered to remove CD33 expression (VOR33 product). Mylotarg™ will be given after engraftment for up to 4 cycles. The primary endpoint assessing safety of VOR33 will be the incidence of successful engraftment at 28 days. Part 1 of this study will evaluate the safety of escalating Mylotarg™ dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 will expand the number of participants to evaluate the Mylotarg™ RP2D.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must be ≥18 and ≤70 years of age.
- •Patients with AML must have one of the following groups of features that are known to be a risk factor for leukemia relapse:
- •BM in morphological remission (<5% blasts) with adverse-risk disease related genetics at presentation (according to European Leukemia-Net guidelines [ELN, Döhner 2017]), or
- •Intermediate risk genetics in morphologic remission (<5% blasts) with other recognized high risk criteria such as MRD+ following therapy, or
- •BM with evidence of persistent leukemia 5-10% blasts post induction/salvage therapy. Patients with BM Blast count >10% may participate with Sponsor Medical Monitor approval. (Note: these patients may have disease-related genetics of any risk criteria at presentation), or
- •Any patient in second or greater remission.
- •Patients with MDS must have all of the following:
- •Previous or current IPSS-R score of High or Very High risk; AND
- •Previous or current MDS-IB1 or MDS-IB2 per the 2022 WHO criteria (Khoury 2022)
- •AML sample from the patient must have evidence of CD33 expression (>0%)
- •Candidate for HLA-matched allogeneic HCT using a myeloablative conditioning regimen.
- •Must have a related or unrelated stem cell donor that is a 8/8 match for HLA-A, -B, -C, and -DRB
- •Must have adequate performance status and organ function as defined below:
- •Performance Status: Karnofsky score of ≥
- •Cardiac: left ventricular ejection fraction (LVEF) ≥50%
- •Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%.
- •Renal: estimated glomerular filtration rate (GFR) >60 mL/min
- •Hepatic: total bilirubin <1.5 × ULN, or if ≥1.5 × ULN direct bilirubin <ULN and ALT/AST <1.5 × ULN (per institutional criteria).
排除标准
- •Prior autologous or allogeneic stem cell transplantation.
- •Presence of the following disease-related genetics: t(15; 17)(q22; q21), or t(9; 22)(q34; q11), or other evidence of acute promyelocytic leukemia or chronic myeloid leukemia.
- •Prior treatment with Mylotarg™ (gemtuzumab ozogamicin) in the past 3.5 months.
- •Active central nervous system (CNS) leukemia.
- •Patients diagnosed with Gilbert's syndrome.
- •Uncontrolled bacterial, viral, or fungal infections; or known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.
研究组 & 干预措施
Cohort 1
VOR33 infusion followed by Mylotarg Dose Level 1
干预措施: VOR33 (Biological)
Cohort 1
VOR33 infusion followed by Mylotarg Dose Level 1
干预措施: Mylotarg (Drug)
Cohort 2
VOR33 infusion followed by Mylotarg Dose Level 2
干预措施: VOR33 (Biological)
Cohort 2
VOR33 infusion followed by Mylotarg Dose Level 2
干预措施: Mylotarg (Drug)
Cohort 3
VOR33 infusion followed by Mylotarg Dose Level 3
干预措施: VOR33 (Biological)
Cohort 3
VOR33 infusion followed by Mylotarg Dose Level 3
干预措施: Mylotarg (Drug)
结局指标
主要结局
Incidence of neutrophil engraftment
时间窗: Day 28
Cumulative incidence of patients who achieve neutrophil engraftment (first day of 3 consecutive days of absolute neutrophil count (ANC) ≥500 cells/mm3) by Day 28.
次要结局
- Incidence of primary and secondary graft failure(Up to 24 months)
- Percentage of CD33-negative myeloid cells(Day 28, 60, 100, 180, and Months 12 and 24)
- Incidence of chronic GVHD (all and moderate-severe)(Up to 24 months)
- Incidence of toxicities to determine the MTD and RP2D of Mylotarg™(Approximately day 60 until 24 months)
- Incidence of transplant-related mortality (TRM) post HCT(Day 100, 12 months, 24 months)
- Relapse-free Survival (RFS)(Months 12 and 24)
- Overall Survival (OS)(Months 12 and 24)
- Time to neutrophil engraftment(Up to approximately 28 days)
- Incidence of acute GVHD Grade (G) G2-G4 and G3-G4(Up to 24 months)
- Time to platelet recovery(Up to approximately 60 days)