Allogeneic Engineered Hematopoietic Stem Cell Transplant (HCT) Lacking the CD33 Protein, and Post-HCT Treatment With Mylotarg, for Patients With CD33+ AML or MDS

Vor Biopharma

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Treatments: Drug: Mylotarg; Biological: VOR33

Study type: Interventional

Funder types: Industry

Identifiers

NCT04849910

VBP101

Details and patient eligibility

About

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).

Full 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.

Enrollment: 24 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. 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

1. 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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24 participants in 3 patient groups

Cohort 1

Experimental group

Description:

VOR33 infusion followed by Mylotarg Dose Level 1

Treatment:

Biological: VOR33

Drug: Mylotarg

Cohort 2

Experimental group

Description:

VOR33 infusion followed by Mylotarg Dose Level 2

Treatment:

Biological: VOR33

Drug: Mylotarg

Cohort 3

Experimental group

Description:

VOR33 infusion followed by Mylotarg Dose Level 3

Treatment:

Biological: VOR33

Drug: Mylotarg