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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Squamous Cell Carcinoma of Head and Neck; Recurrent Head and Neck Squamous Cell Carcinoma; Locally Advanced Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Biological: RP3; Other: CCRT(concurrent chemoradiation therapy); Biological: nivolumab; Other: carboplatin and paclitaxel

Detailed Description

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

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Olomouc, Czechia, 779 00
    • University Hospital Olomouc
  • Prague, Czechia, 140 59
    • Fakultni Thomayerova nemocnice
  • Praha, Czechia, 100 00
    • FN Kralovske Vinohrady
• France
  • Dijon, France, 21079
    • Centre Georges Francois Leclerc, Department of Oncology
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Marseille, France, 13005
    • Assistance Publique Hôpitaux de Marseille
  • Nîmes, France, 30029
    • CHU Nimes, Instiut de Cancerologie du Gard, Medical Oncology
  • Villejuif, France, 94805
    • Institut Gustave Roussy Paris
• Germany
  • Berlin, Germany, 12203
    • Charite University Hospital of Berlin, Comprehensive Cancer Center
  • Jena, Germany, 07747
    • Universitatsklinik Jena Klinik und Poliklinik fur Hals-, Nasen - und Ohrenheilkunde
  • Leipzig, Germany, 04103
    • University Hospital Leipzig Clinic and Polyclinic for otorhinolaryngology
  • Munich, Germany, 81377
    • LMU Klinikum, Medizinische Klinik und Poliklinikum III
  • Ulm, Germany, 89075
    • Universitätsklinikum Ulm
• Greece
  • Chaïdári, Greece, 12462
    • University General Hospital Attikon
  • Thessaloníki, Greece, 55236
    • Agios Lukas Hospital
• Poland
  • Kraków, Poland, 31-826
    • Szpital Specjalistyczny im Ludwika Rydygiera w Krakowie sp z oo, Department of Clinical Oncology
• Spain
  • Barcelona, Spain, 08035
    • Vall d'Hebron University Hospital, Vall d' Hebron Institute of Oncology (VHIO)
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro
  • Madrid, Spain, 28046
    • La Paz Univeristy Hospital, Universidad Autonoma de Madrid
  • Pamplona, Spain, 31008
    • Clinica Universitaria de Navarra
  • Valencia, Spain, 46009
    • Fundación Instituto Valenciano de Oncología
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust
• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego, UCSD
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Medicine Division of Hematology-Oncology
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University City Center and Abington
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center, UPMC
    • Willow Grove, Pennsylvania, United States, 19090
      • Jefferson Health Abington Asplunhd Cancer Pavillion
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington / Fred Hutchinson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LA Cohort: RP3 in combination with CCRT followed by nivolumab in Locally Advanced SCCHN; 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; Genetically modified herpes simplex type 1 virus; Other: CCRT(concurrent chemoradiation therapy); CCRT consisting of intensity modulated radiation therapy combined with a cis-platinum; Biological: nivolumab; anti-PD1 monoclonal antibody
Active Comparator: LA Cohort: concurrent chemoradiation therapy in Patients With Locoregionally Advanced SCCHN; standard-of-care CCRT (defined as intensity-modulated radiation therapy [IMRT] and cisplatin	Other: CCRT(concurrent chemoradiation therapy); CCRT consisting of intensity modulated radiation therapy combined with a cis-platinum
Experimental: R/M Cohort:RP3 in combination with carboplatin, paclitaxel and then nivolumab in R/M SCCHN; 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; Genetically modified herpes simplex type 1 virus; Biological: nivolumab; anti-PD1 monoclonal antibody; Other: carboplatin and paclitaxel; chemotherapeutic agents

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Replimune Inc.
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: David Cohan, MD/FACS, Replimune Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): January 30, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: February 8, 2023
• First Submitted That Met QC Criteria: February 21, 2023
• First Posted (Actual): February 24, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 7, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Immunotherapy; Immuno-oncology; Oncolytic virus; Oncolytic immuno-gene therapy; Squamous cell carcinomas of head and neck
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Recurrence; Carcinoma; Carcinoma, Squamous Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Nivolumab; Carboplatin; Paclitaxel
• Other Study ID Numbers: RP3-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No