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

Study Overview
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Brief Summary
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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.

Detailed Description
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RP3 is a genetically modified herpes simplex type 1 virus (HSV-1) that expresses exogenous genes (anti-CTLA-4 antibody, CD40 ligand and h4-1BBL) designed to directly kill tumor cells and generate a systemic anti-tumor immune response

Official Title
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A Phase 2, Open-label, Multicenter Study Investigating Oncolytic Immunotherapy in Combination With Other Therapy in Patients With Locoregionally Advanced or Recurrent Squamous Cell Carcinoma of the Head and Neck

Conditions
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Squamous Cell Carcinoma of Head and Neck, Locally Advanced Head and Neck Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Biological: RP3
* Other: CCRT(concurrent chemoradiation therapy)
* Other: carboplatin and paclitaxel
* Biological: nivolumab


Participation Criteria
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Eligibility Criteria
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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 site All 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 intent Previously 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 either T3 and/or N2 or greater disease with active smoking and/or greater than 20 pack year smoking history OR T4 and/or N3 disease irrespective of tobacco use SCCHN of unknown primary Stage III/IV irrespective of p16 status or smoking status. Eligible for definitive CCRT with curative intent. R/M Cohort Only Has 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 C Systemic infection requiring intravenous (IV) antibiotics Active 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 pathways History of viral infections according to the protocol Treatment with botanical preparations within 2 weeks prior to treatment. Major surgery ≤ 2 weeks prior to starting study treatment. LA Cohort only Has received prior radiotherapy for SCCHN. Has received any prior systemic therapy for SCCHN. R/M cohort only Is 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LA Cohort: RP3 in combination with CCRT followed by nivolumab in Locally Advanced SCCHN<br>RP3 will be administered via direct intratumoral injection or via CT, ultrasound, or laryngoscopy guided intratumoral injection into superficial, subcutaneous (SC), or nodal lesions and into deeper lesions, including visceral lesions. | Biological: RP3<br>* Genetically modified herpes simplex type 1 virus<br>Other: CCRT(concurrent chemoradiation therapy)<br>* CCRT consisting of intensity modulated radiation therapy combined with a cis-platinum<br>Biological: nivolumab<br>* anti-PD1 monoclonal antibody<br>|
| Active Comparator: LA Cohort: concurrent chemoradiation therapy in Patients With Locoregionally Advanced SCCHN<br>standard-of-care CCRT (defined as intensity-modulated radiation therapy [IMRT] and cisplatin | Other: CCRT(concurrent chemoradiation therapy)<br>* CCRT consisting of intensity modulated radiation therapy combined with a cis-platinum<br>|
| Experimental: R/M Cohort:RP3 in combination with carboplatin, paclitaxel and then nivolumab in R/M SCCHN<br>RP3 will be administered via direct intratumoral injection or via CT, ultrasound, or laryngoscopy guided intratumoral injection into superficial, subcutaneous (SC), or nodal lesions and into deeper lesions, including visceral lesions. | Biological: RP3<br>* Genetically modified herpes simplex type 1 virus<br>Other: carboplatin and paclitaxel<br>* chemotherapeutic agents<br>Biological: nivolumab<br>* anti-PD1 monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LA Cohort: Progression-free Survival | Progression-free survival is defined as the time from the first day of study treatment to the date of progression of disease, which was subsequently confirmed, or death by any cause, whichever occurs first | From Day 1 to documented progression of disease (up to 3 years) | 
| R/M Cohort: Objective Response Rate | Percentage of subjects achieving objective response (complete response + partial response) | From Day 1 to documented progression of disease (up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LA Cohort: Progression-free Survival Rates at 6 and 12 Months | Progression-free survival is defined as the time from the first day of study treatment to the date of progression of disease, which was subsequently confirmed, or death by any cause, whichever occurs first | From Day 1 to documented progression of disease (up to 12 months) | 
| LA Cohort: Overall Survival Rate at 1, 2, and 3 Years | Overall survival is defined as the time from the first day of study treatment to the date of death by any cause | From Day 1 to date of death by any cause (up to 3 years) | 
| LA Cohort: Overall Response Rate and Metabolic Overall Response Rate | Overall Response Rate is the percentage of subjects achieving objective response (complete response + partial response) Metabolic overall response rate is the percentage of subjects achieving objective metabolic response (complete metabolic response + partial metabolic response) | From Day 1 to documented progression of disease (up to 3 years) | 
| LA Cohort: Complete Response Rate and Metabolic Complete Response Rate at 5-and 8-months Following of Initiation of Radiation Following of Initiation of Radiation | Complete response rate is the percentage of subjects achieving complete response Metabolic complete response rate is the percentage of subjects achieving metabolic complete response | From Day 1 to documented progression of disease (up to 8Months Following of Initiation of Radiation) | 
| LA Cohort: Proportion of Patients Achieving No-Evidence-of-Disease Status by Any Means (Including Salvage Surgery) | No-evidence-of-disease is defined as no evidence of malignancy at any site | From Day 1 to end of study (up to 3 years) | 
| LA Cohort: Cumulative Incidence of Locoregional Failure | Locoregional Failure is defined as tumor growth or disease infiltration or spread at the primary tumor location and/or at anatomic areas of local and/or regional disease. | From Day 1 to end of study (up to 3 years) | 
| LA Cohort: Cumulative Incidence of Distant Metastatic Failure | Distant metastatic failure is defined as growth of metastases or new appearance of metastases in lung, bone, liver, other distant organs, and/or distant lymph node stations. | From Day 1 to end of study (up to 3 years) | 
| LA Cohort: Duration of Clinical Benefit | Duration of clinical benefit is defined as the time from the first day of study treatment to last progression of disease, which was subsequently confirmed or with no further follow-up for response, or death due to any cause, whichever occurs first, for subjects who achieve complete response, partial response, or stable disease | From Day 1 to documented progression of disease (up to 3 years) | 
| LA Cohort: Summary of Patient-Reported Outcomes Measured by FACT-HNSI-22 | FACT-HNSI-22 is a Functional Assessment of Cancer Therapy Head & Neck Cancer Symptom Index which consists of 22 items. Each item is scored in a 5 point Likert-type scale: 0=Not at all, 1=A little bit, 2=Some-what, 3=Quite a bit, and 4=Very much. The higher the score, the worse the patient outcome. | From Day 1 to 52 Weeks. | 
| LA Cohort: Summary of Patient-Reported Outcomes Measured by EQ-5D-5L | EQ-5D-5L is a self-assessed, health related, quality of life questionnaire which consists of 2 pages: EQ-5D descriptive system and EQ visual analogue scale (EQ VAS). The EQ-5D descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale which is numbered from 0 to 100. 0 means the worst health the patient can imagine. 100 means the best health the patient can imagine. The higher the score, the better the patient outcome. | From Day 1 to 52 Weeks | 
| LA Cohort: Frequency, Nature, and Severity of TEAEs and SAEs | Percentage of subjects with TEAEs and SAEs | From Screening through 60 days after last dose of RP3, or 100 days after last dose of nivolumab, or 28 days after last dose of either cisplatin, carboplatin, or paclitaxel, whichever occurs last | 
| R/M Cohort: Progression-free Survival | Progression-free survival is defined as the time from the first day of study treatment to the date of progression of disease, which was subsequently confirmed, or death by any cause, whichever occurs first | From Day 1 to documented progression of disease (up to 3 years) | 
| R/M Cohort: Progression-free Survival Rates at 6 and 12 Months | Progression-free survival is defined as the time from the first day of study treatment to the date of progression of disease, which was subsequently confirmed, or death by any cause, whichever occurs first | From Day 1 to documented progression of disease (up to 12 months) | 
| R/M Cohort: Overall Survival Rates at 1, 2, and 3 Years | Overall survival is defined as the time from the first day of study treatment to the date of death by any cause | From Day 1 to date of death by any cause (up to 3 years) | 
| R/M Cohort: Duration of Response | Duration of response is defined as the time from documented response until the date of progression of disease, which was subsequently confirmed or with no further follow-up, or death due to any cause, whichever occurs first | From Day 1 to documented progression of disease (up to 3 years) | 
| R/M Cohort: Duration of Clinical Benefit | Duration of clinical benefit is defined as the time from the first day of study treatment to last progression of disease, which was subsequently confirmed or with no further follow-up for response, or death due to any cause, whichever occurs first, for subjects who achieve complete response, partial response, or stable disease | From Day 1 to documented progression of disease (up to 3 years) | 
| R/M Cohort: Complete Response Rate | Percentage of subjects achieving a complete response | From Day 1 to documented progression of disease (up to 3 years) | 
| R/M Cohort: Disease Control Rate | Percentage of patients achieving complete response, partial response, or stable disease | From Day 1 to documented progression of disease (up to 3 years) | 
| R/M Cohort: Number of Patients Who Undergo Attempted Definitive Resection | Number of Patients Who Undergo Attempted Definitive Resection | From Day 1 to end of study (up to 3 years) | 
| R/M Cohort: Frequency, Nature, and Severity of TEAEs and SAEs | Percentage of subjects with TEAEs and SAEs | From Screening through 60 days after last dose of RP3, or 100 days after last dose of nivolumab, or 28 days after last dose of either cisplatin, carboplatin, or paclitaxel, whichever occurs last | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Squamous cell carcinomas of head and neck, Immunotherapy, Immuno-oncology, Oncolytic virus, Oncolytic immuno-gene therapy