Clinical trial NCT05984199: Donor-Derived Anti-CD33 CAR T Cell Therapy (VCAR33) in Patients With Relapsed or Refractory AML After Allogeneic Hematopoietic Cell Transplant
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
Keywords: Leukemia
Acute Myeloid Leukemia
AML
Hematopoietic stem cell transplant
HCT
CD33
Allogeneic
CAR T
CAR-T
Chimeric Antigen Receptor T Cell
CAR T Cells
CAR-T Cells
Immunotherapy
Lead sponsor: Vor Biopharma
Sponsor class: INDUSTRY
First posted: 2023-08-09
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of dose-limiting toxicities
timeFrame: Day 28
Secondary outcomes:
measure: Incidence of GVHD related to VCAR33
timeFrame: Up to 24 months
measure: Percentage of patients who achieve response
timeFrame: Up to 24 months
measure: Overall survival post-VCAR33 infusion
timeFrame: Up to 24 months
measure: Progression-free survival post-VCAR33 infusion
timeFrame: Up to 24 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute Emory University
state: Georgia
city: Fairway
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Bethesda
country: United States
facility: National Institutes of Health, Clinical Center
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Health
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine Siteman Cancer Center
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Cleveland
country: United States
facility: University Hospitals Seidman Cancer Center
state: Ohio
city: Salt Lake City
country: United States
facility: University of Utah Huntsman Cancer Institute
state: Utah
Study officials:
References: