Intratumoral Delivery of Viral Replicon (saRNA) Particles Expressing IL-12 in Head and Neck Cancer

Study of Intratumoral Injections of VLPONC-01 in Head and Neck Cancer

The goal of this clinical trial is to assess the safety and tolerability of a virus replicon particle (VRP) encapsulated saRNA encoding IL-12 when injected into in head and neck cancer patients. The main questions being addressed are:

The safety and tolerability of intratumoral (IT) injections of VRP-encapsulated saRNA encoding IL-12 (VLPONC-01)

The tumor response to IT injections of VLPONC-01

The tumor response due to the combination of IT injections of VLPONC-01 and system IV administration of neoadjuvant pembrolizumab (anti-PD-1) treatment

Researchers will compare neoadjuvant pembrolizumab alone to the combination therapy to see if the combination enhances tumor responses.

The study is an Open label, Phase I study to determine the safety of IT injected VLPONC-01 as a therapeutic agent in subjects with non-resectable and resectable Head and Neck Cancer Squamous Cell Carcinomas (HCSCC), and secondarily to assess pathologic response and radiological response (assessed by RECIST 1.1 criteria) in the primary tumor and regional lymph nodes. Researchers also will explore tumor microenvironment changes in cytokine levels and cellular responses.

There will be three distinct cohorts enrolling sequentially:

Cohort A: Researchers will enroll unresectable or recurrent/metastatic head and neck cancer with at least 1 injectable tumor not scheduled for tumor resection surgery who will receive four doses of VLPONC-01.

Cohort C: Researchers will enroll HCSCC patients scheduled for tumor resection surgery who will receive four doses of VLPONC-1 and two doses of neoadjuvant pembrolizumab or only two doses of neoadjuvant pembrolizumab prior to tumor resection surgery.

Inclusion Criteria:

1. Cohort A - Unresectable or recurrent/metastatic head and neck cancer with at least 1 injectable tumor not scheduled for tumor resection surgery. With one the following prior treatments:

   Subjects must have received a platinum containing chemotherapy regimen, 5-Fluorouracil chemotherapy, taxane based chemotherapy, cetuximab or gemcitabine for treatment of primary tumor in locally advanced, or metastatic settings.

   Subjects must have received an anti-PD-1/ PD-L1 as monotherapy or in combination with chemotherapy.

   Subjects must have progressed following therapy with at least one PD-1 or PD-L1 checkpoint inhibitor (regardless of PD-L1 expression status).

   Prior progression on a PD-1 or PD-L1 checkpoint inhibitor should be unequivocal; progression that occurs within the first 8 weeks of treatment on these agents should be confirmed with a second CT at least 4 weeks apart (to exclude pseudo-progression).

   Patients with activating EGFR mutation or ALK rearrangement which is expected to be responsive to available tyrosine kinase inhibitor therapy, therefore these subjects must have been previously treated with an applicable tyrosine kinase inhibitor.

   OR Cohort C - Patients with at least 1 measurable resectable lesion clinical stage I-IVb (cT1-4, N0-3) (AJCC, 8th Edition) (Amin, 2017), Histologically or cytologically confirmed HNSCC. Scheduled to undergo tumor surgical resection of the primary tumor.

2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate bone marrow and organ function.

3. Primary tumors should be amenable to intratumoral (IT) injection >1 cm diameter. This will be determined by the Protocol Director, or the surgeon involved.

4. Subjects with either a local recurrence or a new primary tumor will be allowed.

5. Age ≥ 18 years.

6. Have acceptable organ and marrow function defined as follows:

   Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Hemoglobin ≥ 8.0 g/dL (Note: use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable) Total bilirubin ≤2x institutional upper limit of normal (ULN) AST(SGOT) or ALT(SGPT) ≤ 3.0x institutional ULN

7. Ability to understand and the willingness to provide written informed consent.

8. Life expectancy > 12 weeks (about 3 months).

9. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

1. Tumors which are not feasible for injections include high risk lesions that are near vital organs or important neurovascular structures, as determined by the Protocol Director or involved surgeon.
2. Women of childbearing potential must have a negative serum β-hCG pregnancy test within 7 days prior to the administration of the first study treatment and/or urine pregnancy 48 hours prior to the administration of the first study treatment. Both sexually active women of childbearing potential and males (and their female partners) patients must agree to use two methods of effective contraception, one of them being a barrier method, or to abstain from sexual activity during the study and for at least 6 months after last dose of study drugs.
3. Patients expected to receive other anti-cancer medication such as, chemotherapy, immunotherapy, biologic therapy, targeted therapy, monoclonal antibodies, hormonal therapy (other than leuprolide or other GnRH agonists) prior to surgery and where all acute toxicity of prior treatments have not resolved.
4. Participation in another clinical study with an investigational product during the last 30 days.
5. Uncontrolled intercurrent illness including, that do not respond to active medical intervention.
6. Current or prior use of immunosuppressive medication within 28 days before the first dose of injection, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone or an equivalent corticosteroid.
7. If applicable: Women who are breastfeeding.
8. History of allogenic organ transplant that requires use of immunosuppressives.
9. Subject has active or uncontrolled infection including known HIV infection or known chronic hepatitis B or C.
10. Any condition that, in the investigator's opinion, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
11. Uncontrolled intercurrent illness including those that do not respond to active medical intervention.
12. Any contraindication to the use of known history of hypersensitivity to any immune therapy's drugs.