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

Sponsor

Vor Biopharma (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05984199

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

2.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute	Biological: VCAR33	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Nov 1, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Incidence of dose-limiting toxicities [Day 28]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients aged ≥18 years
Patients must have CD33+ AML in relapse or refractory after alloHCT
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.
Disease status at the time of enrollment:
Arm A/Morphologic disease: Defined as ≥ 5% blasts (bone marrow) post-HCT
Arm B/MRD positive: < 5% blasts (bone marrow) with minimal residual disease of at least 0.1% CD33+ leukemia cells by flow cytometry
Performance status: ECOG 0 or 1
Patient must have adequate organ function as defined by:
Cardiac: Left ventricular ejection fraction (LVEF) ≥ 45% or fractional shortening ≥ 28%
Pulmonary: Baseline oxygen saturation > 92% on room air at rest
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
Renal: Serum creatinine must be ≤ 1.2x institutional ULN or creatinine clearance ≥ 60 mL/min for patients with creatinine levels above institutional normal
Original alloHCT donor is available and willing to undergo apheresis

Exclusion Criteria:

Patients who have undergone more than one alloHCT
Patients who have undergone alloHCT with a mismatched unrelated donor, haploidentical donor, or with umbilical cord blood as the stem cell source
Patients who will be less than 100 days post-alloHCT at the time of VCAR33 infusion.
Patients with any history of Grade III or IV acute GVHD or severe chronic GVHD unless approved by the Sponsor Medical Monitor
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.
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.
Patients with the following prior therapy:
DLI within 28 days prior to enrollment
Prior treatment with any CAR T cell therapy product
Patients with active or uncontrolled viral, bacterial, or fungal infection
Patients with a history of a human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection
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
Female patients of childbearing potential who are pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego Moores Cancer Center	La Jolla	California	United States	92093
2	Stanford Cancer Institute	Stanford	California	United States	94305
3	Miami Cancer Institute	Miami	Florida	United States	33176
4	The University of Kansas Cancer Center	Fairway	Kansas	United States	66205
5	University of Michigan Health	Ann Arbor	Michigan	United States	48109
6	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
7	Washington University School of Medicine Siteman Cancer Center	Saint Louis	Missouri	United States	63110
8	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
9	University Hospitals Seidman Cancer Center	Cleveland	Ohio	United States	44106
10	University of Utah Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112