Allogeneic Engineered Hematopoietic Stem Cell Transplant (HCT) Lacking the CD33 Protein, and Post-HCT Treatment With Mylotarg, for Patients With CD33+ AML or MDS
Purpose
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).
Conditions
- Leukemia, Myeloid, Acute
- Myelodysplastic Syndromes
Eligibility
- Eligible Ages
- Between 18 Years and 70 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Must be ≥18 and ≤70 years of age. 2. 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. 3. 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) 4. AML sample from the patient must have evidence of CD33 expression (>0%) 5. Candidate for HLA-matched allogeneic HCT using a myeloablative conditioning regimen. 6. Must have a related or unrelated stem cell donor that is a 8/8 match for HLA-A, -B, -C, and -DRB1. 7. Must have adequate performance status and organ function as defined below: 1. Performance Status: Karnofsky score of ≥70. 2. Cardiac: left ventricular ejection fraction (LVEF) ≥50% 3. Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%. 4. Renal: estimated glomerular filtration rate (GFR) >60 mL/min 5. Hepatic: total bilirubin <1.5 × ULN, or if ≥1.5 × ULN direct bilirubin <ULN and ALT/AST <1.5 × ULN (per institutional criteria).
Exclusion Criteria
- Prior autologous or allogeneic stem cell transplantation. 2. 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. 3. Prior treatment with Mylotarg™ (gemtuzumab ozogamicin) in the past 3.5 months. 4. Active central nervous system (CNS) leukemia. 5. Patients diagnosed with Gilbert's syndrome. 6. Uncontrolled bacterial, viral, or fungal infections; or known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.
Study Design
- Phase
- Phase 1/Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Cohort 1 |
VOR33 infusion followed by Mylotarg Dose Level 1 |
|
|
Experimental Cohort 2 |
VOR33 infusion followed by Mylotarg Dose Level 2 |
|
|
Experimental Cohort 3 |
VOR33 infusion followed by Mylotarg Dose Level 3 |
|
Recruiting Locations
Fairway, Kansas 66205
More Details
- Status
- Recruiting
- Sponsor
- Vor Biopharma
Detailed Description
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.