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

• ClinicalTrials.gov Identifier: NCT04849910
• Recruitment Status: Recruiting
• First Posted: April 19, 2021
• Last Update Posted: February 1, 2023
• Sponsor: Vor Biopharma
• Information provided by (Responsible Party): Vor Biopharma

Tracking Information

• First Submitted Date: March 25, 2021
• First Posted Date: April 19, 2021
• Last Update Posted Date: February 1, 2023
• Actual Study Start Date: December 16, 2021
• Estimated Primary Completion Date: May 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 16, 2021)

Incidence of neutrophil engraftment [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 16, 2021)

• Time to neutrophil engraftment [ Time Frame: 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.
• Time to platelet recovery [ Time Frame: Up to approximately 60 days ]
  Time to platelet recovery defined as time from Day 0 to achieve platelet count ≥20,000/μL without transfusion in prior 7 days.
• Incidence of acute GVHD Grade (G) G2-G4 and G3-G4 [ Time Frame: Up to 24 months ]
• Incidence of chronic GVHD (all and moderate-severe) [ Time Frame: Up to 24 months ]
• Incidence of primary and secondary graft failure [ Time Frame: 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.
• Incidence of toxicities to determine the MTD and RP2D of Mylotarg™ [ Time Frame: Approximately day 60 until 24 months ]
• Incidence of transplant-related mortality (TRM) post HCT [ Time Frame: Day 100, 12 months, 24 months ]
• Percentage of CD33-negative myeloid cells [ Time Frame: Day 28, 60, 100, 180, and Months 12 and 24 ]
  Percent donor myeloid chimerism and CD33-negative myeloid cells in peripheral blood.
• Relapse-free Survival (RFS) [ Time Frame: Months 12 and 24 ]
  Cumulative incidence of RFS
• Overall Survival (OS) [ Time Frame: Months 12 and 24 ]
  OS defined as the time from HCT to the date of death from any cause

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Allogeneic Engineered Hematopoietic Stem Cell Transplant (HCT) Lacking the CD33 Protein, and Post-HCT Treatment With Mylotarg, for Patients With CD33+ AML
• 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
• Brief Summary: This is a Phase 1/2a, multicenter, open-label, first-in-human (FIH) study of VOR33 in participants with AML who are undergoing human leukocyte antigen (HLA)-matched allogeneic hematopoietic cell transplant (HCT).
• Detailed Description: High risk acute myeloid leukemia (AML) 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 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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia, Myeloid, Acute

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
  Other Name: gemtuzumab ozogamicin

Study Arms

• Experimental: Cohort 1
  VOR33 infusion followed by Mylotarg Dose Level 1
  Interventions:

  • Biological: VOR33
  • Drug: Mylotarg
• Experimental: Cohort 2
  VOR33 infusion followed by Mylotarg Dose Level 2
  Interventions:

  • Biological: VOR33
  • Drug: Mylotarg
• Experimental: Cohort 3
  VOR33 infusion followed by Mylotarg Dose Level 3
  Interventions:

  • Biological: VOR33
  • Drug: Mylotarg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 16, 2021): 18
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2025
• Estimated Primary Completion Date: May 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Must be ≥18 and ≤70 years of age.
2. Must have confirmed diagnosis of AML in first or second complete remission (CR1 or CR2) or have bone marrow blasts ≤10% without circulating blasts.
3. AML sample from the patient must have evidence of CD33 expression (>0%)
4. AML must have intermediate or high-risk disease-related genetics and the presence of minimal residual disease (MRD). Subjects in CR2 or with persistent morphologic blasts; may have favorable disease-related genetics.
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 10/10 match for HLA-A, -B, -C, -DRB1 and -DQB1.

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).
4. Active central nervous system (CNS) leukemia or history of other active malignancy(ies).
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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT04849910
• Other Study ID Numbers: VBP101
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Vor Biopharma
• Original Responsible Party: Same as current
• Current Study Sponsor: Vor Biopharma
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Vor Biopharma
• Verification Date: January 2023