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

Phase 1

Recruiting

• Conditions: Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
• Interventions: Biological: VOR33; Drug: Mylotarg

• Registration Number: NCT04849910
• Lead Sponsor: Vor Biopharma

Brief Summary

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).

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 Timeline

• Study First Submitted: 2021-03-25
• Study First Submitted QC: 2021-04-16
• Study First Posted: 2021-04-19
• Study Start: 2021-12-16
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-28
• Last Update Posted: 2024-08-29
• Primary Completion: 2025-02
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 24

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 3	Mylotarg	VOR33 infusion followed by Mylotarg Dose Level 3
Cohort 2	Mylotarg	VOR33 infusion followed by Mylotarg Dose Level 2
Cohort 1	VOR33	VOR33 infusion followed by Mylotarg Dose Level 1
Cohort 3	VOR33	VOR33 infusion followed by Mylotarg Dose Level 3
Cohort 1	Mylotarg	VOR33 infusion followed by Mylotarg Dose Level 1
Cohort 2	VOR33	VOR33 infusion followed by Mylotarg Dose Level 2

Primary Outcome Measures

Name	Time	Method
Incidence of neutrophil engraftment	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.

Secondary Outcome Measures

Name	Time	Method
Relapse-free Survival (RFS)	Months 12 and 24	Cumulative incidence of RFS
Incidence of acute GVHD Grade (G) G2-G4 and G3-G4	Up to 24 months
Incidence of primary and secondary graft failure	Up to 24 months	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.
Percentage of CD33-negative myeloid cells	Day 28, 60, 100, 180, and Months 12 and 24	Percent donor myeloid chimerism and CD33-negative myeloid cells in peripheral blood.
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
Time to neutrophil engraftment	Up to approximately 28 days	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.
Overall Survival (OS)	Months 12 and 24	OS defined as the time from HCT to the date of death from any cause
Time to platelet recovery	Up to approximately 60 days	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.

Trial Locations

Locations (14)

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

University of Utah Huntsman Cancer Institute; 🇺🇸 Salt Lake City, Utah, United States

University of California San Diego Moores Cancer Center; 🇺🇸 La Jolla, California, United States

University Hospitals Seidman Cancer Center; 🇺🇸 Cleveland, Ohio, United States

Stanford Cancer Institute; 🇺🇸 Stanford, California, United States

The University of Kansas Cancer Center; 🇺🇸 Fairway, Kansas, United States

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

Hôpital Maisonneuve-Rosemont; 🇨🇦 Montréal, Quebec, Canada

Masonic Cancer Center, University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

National Institutes of Health, Clinical Center; 🇺🇸 Bethesda, Maryland, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Columbia University Medical Center - Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

Washington University School of Medicine Siteman Cancer Center; 🇺🇸 Saint Louis, Missouri, United States

John Theurer Cancer Center at Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States