Phase 1 Study of GEN2 in Patients with Advanced Solid Tumors

Protocol GVO-1102 is a phase 1, open label, multi-center study in adult patients with locally advanced or metastatic solid tumors. This study includes two parts: dose escalation and dose expansion. In the dose escalation phase, GEN2 will be administered at increasing dose levels via intravenous infusion or intratumoral injection on Days 1, 3 and 8 every 4 weeks. Valganciclovir will start dosing on Day 12 and continue for 10 days (through Day 21). Once a recommended dose has been defined in approximately 35-45 patients, the dose expansion phase will initiate to further assess intravenous administration of GEN2 in specific tumor types. Approximately 15 patients per tumor type will be enrolled in the intravenous dose expansion phase.

GEN2 is a non-replicating off-the-shelf gene therapy vector product being developed as a cancer immunotherapy to activate a patient's immune system against their personal cancer antigens (neoantigens). The vector payload encodes for a suicide gene, an enhanced viral thymidine kinase enzyme (HSV-eTK), which in the presence of a prodrug, valganciclovir, causes the tumor to release patient specific tumor antigens. These neoantigens in the presence of a human immune modulator cytokine, granulocyte-macrophage colony-stimulating factor (hGM-CSF), results in the generation of immune effector cells. These effector cells maintain continually amplifying therapeutic immune responses as more tumor cells are killed and release antigen and will potentially kill any new tumor metastases that arise.

Eligibility Criteria:
Inclusion Criteria:

* Adult patients with a locally advanced or metastatic solid tumor that has progressed or was non-responsive to prior therapy
* Measurable disease as determined by response evaluation criteria in solid tumors (RECIST) v1.1.
* At least 18 years of age.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 - 1.
* For patients with HCC: Child-Pugh Class A
* Available archived tumor tissue sample or a lesion that can be safely biopsied if the archived sample is not available.
* Adequate renal, liver and bone marrow function.
* Ability to swallow VGCV tablets.
* Willingness of men and women of child-bearing potential (WCBP) to observe conventional and highly effective birth control for the duration of treatment and for 12 months following the last dose of study treatment. Patients who are pregnant or lactating are excluded.
* For the dose expansion phase: Patients with hepatocellular carcinoma or cutaneous malignancy: no more than 2 prior systemic regimens for metastatic disease. Patients with breast cancer: no more than 2 prior cytotoxic regimens for metastatic disease (single-agent hormone therapy or hormone-based doublets do not count). Patients with cutaneous malignancies includes patients with melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma and Merkel cell carcinoma.
* For the intratumoral injection dose escalation phase: patients with cutaneous malignancy, including patients with melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma and Merkel cell carcinoma. Patients must have at least 1 measurable and injectable lesion and an additional site of measurable distant metastases for assessment of systemic immune response to therapy. Patients may not have received prior treatment with oncolytic therapy. Patients for whom tyrosine kinase inhibitor therapy would be considered standard of care should have received these agents prior to enrollment in this trial. Patients may not have a history of significant bleeding diathesis.

Exclusion Criteria:

* Investigational agent or anticancer therapy within 28 days or 5 elimination half-lives prior to Cycle 1 Day 1.
* Prior receipt of talimogene laherparepvec (TVEC) or any other oncolytic virus (including but not limited to RP1, RP2, or BNT111).; prior receipt of a live vaccine within 28 days prior to Cycle 1 Day 1.
* Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of enrollment (alopecia and other nonacute toxicities are not exclusionary)
* Washout from prior major surgery and radiotherapy (less than 28 days)
* Symptomatic primary central nervous system (CNS) tumor or metastases; symptomatic leptomeningeal carcinomatosis; untreated spinal cord compression. Patients with CNS lesions may be eligible if CNS lesions are asymptomatic or if neurological symptoms are stable, the patient is not receiving steroids to manage CNS symptoms, and no CNS surgery or radiation has been performed for 28 days (14 days for stereotactic radiation).
* Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the Investigator makes it undesirable for the patient to participate in the trial
* Clinically significant active malabsorption syndrome or other conditions such as refractory nausea and vomiting, external biliary shunt, or significant bowel resection likely to affect gastrointestinal absorption of valganciclovir
* Known contraindications to the ganciclovir class
* For patients with hepatocellular carcinoma, patients with active hepatitis B are excluded; patients with evidence of prior exposure who have a negative hepatitis surface antigen (HbsAg) and who do not require antiviral therapy are allowed. Patients with hepatitis C are allowed but may not be on antiviral therapy during study participation and for two weeks prior to Cycle 1 Day 1.
* Known HIV positivity
* Current treatment with systemic steroids at or above 10 mg/day of prednisone (or its equivalent). Inhalational and topical steroids are acceptable