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
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Vor Biopharma
- Enrollment
- 38
- Locations
- 14
- Primary Endpoint
- Incidence of dose-limiting toxicities
Study Overview
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).
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
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
MRD Positive: Cohort 2
VCAR33 Dose Level 2
Intervention: VCAR33 (Biological)
Morphologic Disease: Cohort 1
VCAR33 Dose Level 1
Intervention: VCAR33 (Biological)
Morphologic Disease: Cohort 2
VCAR33 Dose Level 2
Intervention: VCAR33 (Biological)
Morphologic Disease: Cohort 3
VCAR33 Dose Level 3
Intervention: VCAR33 (Biological)
MRD Positive: Cohort 1
VCAR33 Dose Level 1
Intervention: VCAR33 (Biological)
MRD Positive: Cohort 3
VCAR33 Dose Level 3
Intervention: VCAR33 (Biological)
Outcomes
Primary Outcomes
Incidence of dose-limiting toxicities
Time Frame: Day 28
Secondary Outcomes
- Overall survival post-VCAR33 infusion(Up to 24 months)
- Percentage of patients who achieve response(Up to 24 months)
- Progression-free survival post-VCAR33 infusion(Up to 24 months)
- Incidence of GVHD related to VCAR33(Up to 24 months)