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

Myelodysplastic Syndromes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04849910
• Other study ID #: VBP101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 16, 2021
• Est. completion date: January 2027

Study information

• Verified date: May 2024
• Source: Vor Biopharma
• Contact: Glen Raffel, MD, PhD
• Phone: 6176556580
• Email: clinicaltrials[@]vorbio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: January 2027
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Canada	Hôpital Maisonneuve-Rosemont	Montréal	Quebec
United States	National Institutes of Health, Clinical Center	Bethesda	Maryland
United States	University Hospitals Seidman Cancer Center	Cleveland	Ohio
United States	The University of Kansas Cancer Center	Fairway	Kansas
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	University of California San Diego Moores Cancer Center	La Jolla	California
United States	Miami Cancer Institute	Miami	Florida
United States	Columbia University Medical Center - Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Washington University School of Medicine Siteman Cancer Center	Saint Louis	Missouri
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Vor Biopharma

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Incidence of acute GVHD Grade (G) G2-G4 and G3-G4		Up to 24 months
Secondary	Incidence of chronic GVHD (all and moderate-severe)		Up to 24 months
Secondary	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
Secondary	Incidence of toxicities to determine the MTD and RP2D of Mylotarg™		Approximately day 60 until 24 months
Secondary	Incidence of transplant-related mortality (TRM) post HCT		Day 100, 12 months, 24 months
Secondary	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
Secondary	Relapse-free Survival (RFS)	Cumulative incidence of RFS	Months 12 and 24
Secondary	Overall Survival (OS)	OS defined as the time from HCT to the date of death from any cause	Months 12 and 24