Study of RP3 in Combination With Nivolumab and Other Therapy in Patients With Locoregionally Advanced or Recurrent SCCHN

This is a Phase 2, multicenter, open-label, 2-cohort (Locoregionally Advanced Cohort or Recurrent/Metastatic Cohort) study evaluating RP3 in combination with concurrent chemoradiation therapy (CCRT) followed by nivolumab (for the LA Cohort) or combined with chemotherapy and nivolumab (for the R/M Cohort) in patients with advanced, inoperable squamous cell carcinomas of the head and neck (SCCHN), including of the oral cavity, oropharynx, hypopharynx, larynx, or unknown primary.

Inclusion Criteria:Histological diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx or of a lymph node(s) anywhere in levels I to V of the neck that has been excluded clinically from association with cancer from a non-head and neck siteAll patients Must be willing to consent to provide archival or fresh tumor biopsy samples obtained within 60 days prior to initiation of study treatment. Patients must also consent to provide on-treatment biopsies as per protocol.At least 1 measurable lesion of ≥ 1 cm in longest diameter (or shortest diameter for lymph nodes), in accordance with RECIST.At least injectable tumors of at least 1 cm in aggregate overall longest diameter.Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 -1.Locally Advanced Cohort Only• patients must not be amenable to surgery with curative intentPreviously untreated high-risk disease meeting at least 1 of the following criteria:Oral cavity, hypopharynx, larynx, oropharynx (p16 negative): Stage III/ IV Note: Cancers of the oral cavity, hypopharynx, and larynx are eligible irrespective of p16 status. These patients will not be stratified by p16 status.For p16 positive oropharynx cancers, patients must have eitherT3 and/or N2 or greater disease with active smoking and/or greater than 20 pack year smoking history ORT4 and/or N3 disease irrespective of tobacco useSCCHN of unknown primary Stage III/IV irrespective of p16 status or smoking status.Eligible for definitive CCRT with curative intent.R/M Cohort OnlyHas recurrent or metastatic SCCHN eligible for first line systemic therapy for R/M disease.Has a PD-L1 CPS <20.Exclusion Criteria:Primary tumors of nasopharynx, paranasal sinuses, nasal passages, salivary gland, thyroid or parathyroid gland, or skin.Tumors with histopathology indicating the tumor has sarcomatous, sarcomatoid, verrucous, mixed, undifferentiated, or otherwise nonsquamous components.Has an airway that is not deemed safe and stable on flexible fiberoptic laryngoscopy (FFL) performed by a head & neck cancer specialist within 7 days of first RP3 injection.Has a baseline serum albumin (at Screening) <2.5 g/dL and/or evidence of cachexia or muscle wasting during physical exam at Screening.Known acute or chronic hepatitis B or acute or chronic hepatitis CSystemic infection requiring intravenous (IV) antibioticsActive significant herpetic infections or prior complications of HSV-1 infection (eg, herpetic keratitis or encephalitis)History of interstitial lung disease.History of (noninfectious) pneumonitis that required steroids or has current pneumonitis.Patients who require intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).Administration of live vaccine within 28 days prior to the first dose of study treatment.History of allergy or sensitivity to study drug components or prior monoclonal antibody treatment.History of life-threatening toxicity related to prior immune treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathwaysHistory of viral infections according to the protocolTreatment with botanical preparations within 2 weeks prior to treatment.Major surgery ≤ 2 weeks prior to starting study treatment.LA Cohort onlyHas received prior radiotherapy for SCCHN.Has received any prior systemic therapy for SCCHN.R/M cohort onlyIs eligible for radiation and/or surgery with curative intent.Has received systemic therapy for recurrence or new (ie, not present at the time of initial diagnosis) metastases of SCCHN.Received a paclitaxel-containing regimen as part of frontline treatment (prior to R/M disease) with a documented best response of stable disease (SD) or PD (patients who achieved a partial response [PR] or CR are eligible).Received a carboplatin-containing regimen as part of frontline treatment (prior to R/M disease) with a documented best response of SD or PD (patients who achieved PR or CR are eligible).Patients with known intolerance to carbo-platinum and/or paclitaxel, including hypersensitivity to Cremophor® EL (polyoxyethylated castor oil).Previously received multiple courses of irradiation to the same anatomic site unless such patient has nondoubly-irradiated, measurable, injectable lesions, which are the only lesions to be used as target lesions (for nodal disease, only lesions in nodal basins that have been previously irradiated just once or not irradiated at all may be injected and/or used as target lesions).Note: Other protocol defined inclusion/exclusion criteria apply for each cohort