Gene Therapy for CD19-Positive Hematologic Malignancies (SENTRY-CD19)

A Phase 1/2 Safety, Dose-finding, and Pharmacokinetics Study of VNX-101 Gene Therapy in Patients With Relapsed or Refractory CD19-Positive Hematologic Malignancies (SENTRY-CD19)

This is a Phase 1/2, first-in-human, open-label, dose-escalating trial designed to assess the safety and efficacy of VNX-101 in patients with relapsed or refractory CD19-positive hematologic malignancies.

VNX-101 is an investigational adeno-associated virus (AAV) gene therapy developed to express a secreted anti-CD19/anti-CD3 scFv diabody (termed GP101). GP101 binds both cluster of differentiation (CD)19 and CD3, inducing T-cells to kill both benign and malignant B-cells. Following a single intravenous (IV) infusion, the vector induces the liver and key tissues to continuously secrete GP101 into the bloodstream, resulting in long-term, consistent serum levels of GP101. Potential advantages of VNX-101 over autologous CAR-T therapy include it is off-the-shelf, provides a gentle onset of action, does not require lymphodepletion chemotherapy, engages all T-cells continuously (including those freshly produced from the bone marrow), and utilizes highly efficient signaling through the native T-cell receptor.

In this 2-part study, dose-finding data from Part 1 of the study (n=~12 patients) will be used determine the dose for Part 2 in patients. Part 1 is a dose-finding PK study in adults ≥18 years old designed to determine the minimal dose that achieves target PK serum levels of GP101 at steady state (8-week timepoint) without dose-limited toxicities, defined as the recommended Part 2 dose (RP2D). Prior to VNX-101 dosing, subjects may undergo standard of care chemotherapy to meet dosing criteria. Part 2 (n=~20) will be opened following data safety monitoring board review of Part 1 data and is designed to determine the safety and pharmacokinetics (PK) of VNX-101 at the RP2D in a broader array of subjects. The age range for Part 2 will be expanded to include subjects ≥13 years old. Patients will be followed for safety and efficacy up to 5 years post VNX-101 dosing. Long-term follow-up assessments for safety will be conducted for 6 to 15 years post VNX-101 dosing.

Inclusion Criteria:

• Age: Part 1: 18-90 years of age, Part 2: 13-90 years of age
• Relapsed or refractory CD-19 positive leukemia or lymphoma as defined in the protocol
• CD19-positive expression
• AAV specified capsid total antibody <1:400
• Protocol-specified ranges for renal, liver, cardiac and pulmonary function
• Protocol-specified ranges for hematology parameters

Exclusion Criteria:

• Hepatoxicity (AST or ALT > 2x upper limit of normal)
• History of thrombotic microangiopathy or cardiomyopathy, or evidence of sensory neuropathy
• Pregnant or nursing (lactating) women
• Acute Graft versus Host Disease (GvHD): Grade 2-4 or chronic GvHD of any grade
• History of hypersensitivity to corticosteroids or history of corticosteroid-related toxicity
• Chemotherapy given within the protocol-specified discontinuation timelines

Other Inclusion/Exclusion criteria to be applied per protocol.