A phase 2, open-label, multicenter study investigating efficacy and safety of RP3 oncolytic immunotherapy combined with other therapies in patients with locoregionally advanced or recurrent squamous cell carcinoma of the head and neck.
Authors: Harrington Kevin Joseph , Cohen Ezra , Zandberg Dan Paul , Day Terry A. , Geiger Jessica Lyn , Oliva Marc , Mesia Ricard , Cohan David Michael 
Published: June 2023

TPS6106 Background: Head and neck (HN) cancers were estimated to account for > 50,000 new cancer diagnoses and > 11,000 deaths in the US in 2022. Squamous cell carcinoma of the head and neck (SCCHN) comprises about 90% of HN cancers. For locally advanced (LA) SCCHN, standard initial therapy is concurrent chemoradiation therapy (CCRT) or definitive resection followed by adjuvant radiation ± chemotherapy; > 50% of patients (pts) relapse within 2 years. For recurrent/metastatic (R/M) SCCHN, standard first-line therapy includes immune checkpoint inhibitors (anti–PD-1) ± chemotherapy or cetuximab, chemotherapy ± cetuximab, or salvage surgery; prognoses are poor, and benefit of anti–PD-1 therapy is generally limited to pts with positive PD-L1 combined positive score (CPS). RP3 is an enhanced potency, modified version of herpes simplex virus type 1 expressing the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R−), an anti–CTLA-4 antibody-like molecule, and costimulatory CD40- and 4-1BB–activating ligands. Intratumoral (IT) RP3 delivery may promote immunogenic tumor cell death and systemic antitumor response (abscopal effect), both of which may be further enhanced by standard therapies (eg, chemotherapy, anti–PD-1). This phase 2 study will evaluate the efficacy and safety of RP3 combined with other therapies in pts with advanced, inoperable LA or R/M SCCHN. Methods: Pts in the LA cohort (up to ~100 pts) must have inoperable, previously untreated, high-risk SCCHN eligible for curative intent CCRT and will be randomized 1:1 to receive RP3 + standard of care cisplatin-based CCRT, followed by nivolumab (nivo), vs CCRT alone. A formal safety assessment will be performed 3 weeks after the tenth patient randomized to RP3 + CCRT + nivo has completed CCRT. RP3 will be injected IT into primary tumor sites and/or superficial or deep nodal lesions. Pts in the RP3 group will receive up to 4 doses of RP3 every 3 weeks (Q3W; first dose at a concentration of 1 × 106 plaque-forming units [PFU]/mL; subsequent doses 1 × 107 PFU/mL). Nivo will be given at 240 mg Q2W or 480 mg Q4W (after CCRT completion, concurrent with fourth RP3 dose, for up to 1 year). The primary endpoint for the LA cohort is progression-free survival. Pts in the R/M cohort (up to ~30 pts) must have R/M SCCHN eligible for first-line systemic therapy for locoregional recurrence and/or distant metastases and PD-L1 CPS < 20, and will receive RP3 + nivo + carboplatin/paclitaxel. RP3 will be injected IT as described above for up to 8 doses Q3W (first dose 1 × 106 PFU/mL; subsequent doses 1 × 107 PFU/mL; carboplatin/paclitaxel started at first RP3 dose). Nivo will be given as above, concurrent with third RP3 dose, for up to 2 years. The primary endpoint for the R/M cohort is overall response rate. Clinical trial information: NCT05743270 .