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

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

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).

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
• Intervention / Treatment: Biological: VOR33; Drug: Mylotarg

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.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H1T2M4
      • Hôpital Maisonneuve-Rosemont
• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego Moores Cancer Center
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
  • Florida
    • Miami, Florida, United States, 33176
      • Miami Cancer Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute Emory University
  • Kansas
    • Fairway, Kansas, United States, 66205
      • The University of Kansas Cancer Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health, Clinical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Siteman Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center - Herbert Irving Comprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Seidman Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; VOR33 infusion followed by Mylotarg Dose Level 1	Biological: VOR33; Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein; Drug: Mylotarg; Infusion of Mylotarg; Other Names: gemtuzumab ozogamicin
Experimental: Cohort 2; VOR33 infusion followed by Mylotarg Dose Level 2	Biological: VOR33; Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein; Drug: Mylotarg; Infusion of Mylotarg; Other Names: gemtuzumab ozogamicin
Experimental: Cohort 3; VOR33 infusion followed by Mylotarg Dose Level 3	Biological: VOR33; Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein; Drug: Mylotarg; Infusion of Mylotarg; Other Names: gemtuzumab ozogamicin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of neutrophil engraftment	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.	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to neutrophil engraftment	Time to neutrophil engraftment after HCT from Day 0; calculated as the first day of 3 consecutive laboratory values obtained on separate days where the ANC is ≥500 cells/mm3.	Up to approximately 28 days
Incidence of acute GVHD Grade (G) G2-G4 and G3-G4		Up to 24 months
Incidence of chronic GVHD (all and moderate-severe)		Up to 24 months
Incidence of primary and secondary graft failure	Incidence of primary and secondary graft failure measured by day 28 post HCT. Secondary graft failure is defined as initial neutrophil engraftment by Day 28 followed by subsequent decline.	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
Percentage of CD33-negative myeloid cells	Percent donor myeloid chimerism and CD33-negative myeloid cells in peripheral blood.	Day 28, 60, 100, 180, and Months 12 and 24
Relapse-free Survival (RFS)	Cumulative incidence of RFS	Months 12 and 24
Overall Survival (OS)	OS defined as the time from HCT to the date of death from any cause	Months 12 and 24
Time to platelet recovery	Time to platelet recovery defined as first day of a sustained platelet count >20,000/ μL with no platelet transfusion in the preceding seven days.	Up to approximately 60 days

Collaborators and Investigators

• Sponsor: Vor Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2021
• Primary Completion (Actual): May 28, 2025
• Study Completion (Actual): May 28, 2025

Study Registration Dates

• First Submitted: March 25, 2021
• First Submitted That Met QC Criteria: April 16, 2021
• First Posted (Actual): April 19, 2021

Study Record Updates

• Last Update Posted (Actual): July 29, 2025
• Last Update Submitted That Met QC Criteria: July 25, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; Leukemia; Allogeneic; MDS; Myelodysplastic Syndromes; Cell therapy; HCT; Hematopoietic stem cell transplant; CD33; Myelodysplastic Syndromes with excess blasts; MDS-EB
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Disease; Hematologic Diseases; Precancerous Conditions; Bone Marrow Diseases; Syndrome; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Immunoconjugates; Immunotoxins; Gemtuzumab
• Other Study ID Numbers: VBP101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No