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

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.

• Dose Level 1, VNX-101 (Genetic): Adeno-associated viral vector encoding the CD3/CD19 Bi-Specific T-Cell Engager (AAV.CD3/CD19), Single IV infusion
• Dose Level 2, VNX-101 (Genetic): Adeno-associated viral vector encoding the CD3/CD19 Bi-Specific T-Cell Engager (AAV.CD3/CD19), Single IV infusion
• Dose Level 3, VNX-101 (Genetic): Adeno-associated viral vector encoding the CD3/CD19 Bi-Specific T-Cell Engager (AAV.CD3/CD19), Single IV infusion
• Dose Level 4, VNX-101 (Genetic): Adeno-associated viral vector encoding the CD3/CD19 Bi-Specific T-Cell Engager (AAV.CD3/CD19), Single IV infusion

Primary outcomes

• Treatment emergent adverse events (TEAEs) and treatment-emergent serious events (TESAEs) [Change from Baseline to Year 5 post dosing]

Secondary outcomes

• Change from baseline in B-cell counts [Change from baseline to year 5 post dosing]
• Change baseline in immunoglobulin levels [Change from baseline to year 5 post dosing]
• Change baseline in antitumor activity [Change from baseline to year 5 post dosing]
• Proportion/duration of subjects achieving response, progression free survival, and disease free survival. [Change from baseline to year 5 post dosing]

Other outcomes

• Exploratory Measure: Change in VNX-101 gene product levels [Change from baseline to year 5 post dosing]
• Exploratory Measure: Change in VNX-101 vector shedding [Change from baseline to year 5 post dosing]

Sex: All, ages: 13 Years to 90 Years

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.

• Vironexis Clinical Trials, Study director, Vironexis Biotherapeutics Inc.