Gene Therapy for HER-Positive Cancer (SENTRY-HER2)

A Phase 1/2, First-in-Human Study of VNX-202 Gene Therapy in Patients With HER2-Positive Cancer

This is a Phase 1/2, first-in-human, open-label, dose-escalating and expansion trial designed to assess the safety and efficacy of VNX-202 in patients with HER2 positive cancers.

VNX-202 is an investigational adeno-associated virus (AAV) gene therapy developed to express a secreted anti-HER2/anti-CD3 scFv diabody (termed GP202). GP202 binds to human epidermal growth factor receptor 2 (HER2) on the surface of cancer cells and to cluster of differentiation (CD)3 on the surface of T cells, inducing the T cells to kill the HER2-positive cancer cells.

Following a single intravenous (IV) infusion, the vector induces the liver to continuously secrete GP202 into the bloodstream, resulting in long-term, consistent serum levels of GP202. Compared with conventionally delivered protein therapies, this gene therapy approach obviates the requirement for episodic dosing and avoids a possible reduction or loss of efficacy associated with trough levels of the protein between treatment cycles.

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 with previously treated metastatic HER2 solid tumors designed to determine the minimal dose that achieves target PK serum levels of GP202 at steady state (8-week timepoint) without dose-limited toxicities, defined as the recommended Part 2 dose (RP2D). Participants must have histologically or cytologically confirmed HER2 positive solid tumor cancers that has progressed during or following previous anti-cancer treatment. Part 2 (n=~15) 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-202 at the RP2D in a broader array of subjects. Part 2 will comprise of participants with early stage HER2-positive tumors who are at risk of disease relapse and/or metastasis despite having received prior systemic and/or local treatment. Each cohort will comprise ≥5 participants (Cohort A: breast cancer; Cohort B: gastric cancer; Cohort C: all otherHER2-positive tumor types). Patients will be followed for safety and efficacy up to 5 years post VNX-202 dosing.

Inclusion Criteria:

• Age: ≥18 years of age
• Histologically or cytologically confirmed diagnosis of HER-2 positive solid tumor as defined in the protocol
• Part 1: presence of advanced or metastatic disease that has progressed during or following previous treatment
• Part 2: Early stage HER-2 positive cancers with high risk for relapse following completion of SOC or after neoadjuvant systemic treatment
• AAV specified capsid total antibody ≤1:400
• ECOG performance status of 0 or 1
• Life expectancy ≥3 months
• 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)
• Known active CNS or leptomeningeal disease
• History of thrombotic microangiopathy or cardiomyopathy, or evidence of sensory neuropathy
• Pregnant or nursing (lactating) women
• History of other malignancy within 5 years prior to screening as defined in protocol
• History of hypersensitivity to corticosteroids or history of corticosteroid-related toxicity Concurrent anti-cancer treatment in another investigational trial