Donor-Derived Anti-CD33 CAR T Cell Therapy (VCAR33) in Patients With Relapsed or Refractory AML After Allogeneic Hematopoietic Cell Transplant

Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients With Relapsed or Refractory Acute Myeloid Leukemia After Allogeneic Hematopoietic Cell Transplantation

This is a Phase 1/2, multicenter, open-label, first-in-human (FIH) study of donor-derived anti-CD33 Chimeric Antigen Receptor (CAR) T cell therapy (VCAR33) in patients with relapsed or refractory Acute Myeloid Leukemia (AML) after human leukocyte antigen (HLA)-matched allogeneic hematopoietic cell transplant (alloHCT).

Study Overview

• Status: Terminated
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Biological: VCAR33

Detailed Description

CD33 is a preferential target for AML CAR T cell therapy due to its surface expression on the majority (>80%) of AML blasts and due to the extensive prior clinical experience demonstrating safety and efficacy of targeting CD33 with Mylotarg (gemtuzumab ozogamicin). VCAR33 is being developed as a potential new treatment for patients with relapsed/refractory (R/R) AML after alloHCT. In this Phase 1/2 trial, the safety and efficacy of lentiviral-transduced CD33-directed CAR T cells (VCAR33) generated from the patient's prior allogeneic stem cell donor will be tested. It is hypothesized that CAR T cell production from healthy donors will not only eliminate delays in production due to lymphopenia but also reduce concerns for suboptimal T cell function from exposure to systemic immunosuppression or chemotherapeutic agents. Approximately 24 eligible patients with R/R AML after alloHCT will be enrolled in one of two separate arms based on disease burden (morphologic disease versus measurable residual disease (MRD ) positive). The maximum tolerated dose of VCAR33 will be determined using a 3+3 trial design within each arm. Dose escalation can only occur after a minimum of 3 patients have completed the dose-limiting toxicity (DLT) observation period.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • 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
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • 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, 10029
      • Icahn School of Medicine at Mount Sinai
  • 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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients aged ≥18 years
2. Patients must have CD33+ AML in relapse or refractory after alloHCT
3. Patients must be a recipient of an 8/8 (A, B, C, DRB1) HLA-matched related or unrelated donor alloHCT. Patients previously transplanted with VOR33 in the VBP101 study who have R/R AML may also be considered.

4. Disease status at the time of enrollment:

   1. Arm A/Morphologic disease: Defined as ≥ 5% blasts (bone marrow) post-HCT
   2. Arm B/MRD positive: < 5% blasts (bone marrow) with minimal residual disease of at least 0.1% CD33+ leukemia cells by flow cytometry
5. Performance status: ECOG 0 or 1

6. Patient must have adequate organ function as defined by:

   1. Cardiac: Left ventricular ejection fraction (LVEF) ≥ 45% or fractional shortening ≥ 28%
   2. Pulmonary: Baseline oxygen saturation > 92% on room air at rest
   3. Hepatic: Total bilirubin < 3x institutional upper limit of normal (ULN) (except in case of patients with documented Gilbert's disease < 5x ULN) and aspartate aminotransferase (AST/SGOT)/alanine aminotransferase (ALT/SGPT) < 5x institutional ULN
   4. Renal: Serum creatinine must be ≤ 1.2x institutional ULN or creatinine clearance ≥ 60 mL/min for patients with creatinine levels above institutional normal
7. Original alloHCT donor is available and willing to undergo apheresis

Exclusion Criteria:

1. Patients who have undergone more than one alloHCT
2. Patients who have undergone alloHCT with a mismatched unrelated donor, haploidentical donor, or with umbilical cord blood as the stem cell source
3. Patients who will be less than 100 days post-alloHCT at the time of VCAR33 infusion.
4. Patients with any history of Grade III or IV acute GVHD or severe chronic GVHD unless approved by the Sponsor Medical Monitor
5. Patients with evidence of ongoing active acute or chronic GVHD and are taking systemic immunosuppressive agents (> 10 mg daily of prednisone equivalent or other GVHD-directed treatment, including extracorporeal photopheresis). Patients with Grade 1 acute GVHD limited to the skin or mild chronic GVHD limited to the eyes, mouth, or skin controlled with only topical therapy are eligible.
6. Patients with active CNS disease. A lumbar puncture is not required to exclude CNS disease in the absence of clinical signs or symptoms suggesting CNS disease.

7. Patients with the following prior therapy:

   1. DLI within 28 days prior to enrollment
   2. Prior treatment with any CAR T cell therapy product
8. Patients with active or uncontrolled viral, bacterial, or fungal infection
9. Patients with a history of a human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection
10. Patients with a history of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, or breast) unless disease free for at least 3 years after the last definitive therapy
11. Female patients of childbearing potential who are pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Morphologic Disease: Cohort 1; VCAR33 Dose Level 1	Biological: VCAR33; Allogeneic Anti-CD33 Chimeric Antigen Receptor (CAR) T Cell therapy
Experimental: Morphologic Disease: Cohort 2; VCAR33 Dose Level 2	Biological: VCAR33; Allogeneic Anti-CD33 Chimeric Antigen Receptor (CAR) T Cell therapy
Experimental: Morphologic Disease: Cohort 3; VCAR33 Dose Level 3	Biological: VCAR33; Allogeneic Anti-CD33 Chimeric Antigen Receptor (CAR) T Cell therapy
Experimental: MRD Positive: Cohort 1; VCAR33 Dose Level 1	Biological: VCAR33; Allogeneic Anti-CD33 Chimeric Antigen Receptor (CAR) T Cell therapy
Experimental: MRD Positive: Cohort 2; VCAR33 Dose Level 2	Biological: VCAR33; Allogeneic Anti-CD33 Chimeric Antigen Receptor (CAR) T Cell therapy
Experimental: MRD Positive: Cohort 3; VCAR33 Dose Level 3	Biological: VCAR33; Allogeneic Anti-CD33 Chimeric Antigen Receptor (CAR) T Cell therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of dose-limiting toxicities	Day 28

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of GVHD related to VCAR33	Up to 24 months
Percentage of patients who achieve response	Up to 24 months
Overall survival post-VCAR33 infusion	Up to 24 months
Progression-free survival post-VCAR33 infusion	Up to 24 months

Collaborators and Investigators

• Sponsor: Vor Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2023
• Primary Completion (Actual): May 28, 2025
• Study Completion (Actual): May 28, 2025

Study Registration Dates

• First Submitted: July 19, 2023
• First Submitted That Met QC Criteria: August 1, 2023
• First Posted (Actual): August 9, 2023

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; CAR-T; Immunotherapy; AML; Leukemia; Allogeneic; HCT; CAR T; CAR-T Cells; Hematopoietic stem cell transplant; CD33; Chimeric Antigen Receptor T Cell; CAR T Cells
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: VBP301

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