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

Sponsor

Replimune Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05743270

Collaborator

Bristol-Myers Squibb (Industry)

130

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of Head and Neck Locally Advanced Head and Neck Squamous Cell Carcinoma Recurrent Head and Neck Squamous Cell Carcinoma	Biological: RP3 Other: CCRT(concurrent chemoradiation therapy) Other: carboplatin and paclitaxel Biological: nivolumab	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

130 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

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 Other: carboplatin and paclitaxel chemotherapeutic agents Biological: nivolumab anti-PD1 monoclonal antibody

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

Biological: RP3

Genetically modified herpes simplex type 1 virus

Other: carboplatin and paclitaxel

chemotherapeutic agents

Biological: nivolumab

anti-PD1 monoclonal antibody

Outcome Measures

Primary Outcome Measures

LA Cohort: Progression-free Survival [From Day 1 to documented progression of disease (up to 3 years)]
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
R/M Cohort: Objective Response Rate [From Day 1 to documented progression of disease (up to 3 years)]
Percentage of subjects achieving objective response (complete response + partial response)

Secondary Outcome Measures

LA Cohort: Progression-free Survival Rates at 6 and 12 Months [From Day 1 to documented progression of disease (up to 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
LA Cohort: Overall Survival Rate at 1, 2, and 3 Years [From Day 1 to date of death by any cause (up to 3 years)]
Overall survival is defined as the time from the first day of study treatment to the date of death by any cause
LA Cohort: Overall Response Rate and Metabolic Overall Response Rate [From Day 1 to documented progression of disease (up to 3 years)]
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)
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 [From Day 1 to documented progression of disease (up to 8Months 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
LA Cohort: Proportion of Patients Achieving No-Evidence-of-Disease Status by Any Means (Including Salvage Surgery) [From Day 1 to end of study (up to 3 years)]
No-evidence-of-disease is defined as no evidence of malignancy at any site
LA Cohort: Cumulative Incidence of Locoregional Failure [From Day 1 to end of study (up to 3 years)]
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.
LA Cohort: Cumulative Incidence of Distant Metastatic Failure [From Day 1 to end of study (up to 3 years)]
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.
LA Cohort: Duration of Clinical Benefit [From Day 1 to documented progression of disease (up to 3 years)]
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
LA Cohort: Summary of Patient-Reported Outcomes Measured by FACT-HNSI-22 [From Day 1 to 52 Weeks.]
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.
LA Cohort: Summary of Patient-Reported Outcomes Measured by EQ-5D-5L [From Day 1 to 52 Weeks]
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.
LA Cohort: Frequency, Nature, and Severity of 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]
Percentage of subjects with TEAEs and SAEs
R/M Cohort: Progression-free Survival [From Day 1 to documented progression of disease (up to 3 years)]
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
R/M Cohort: Progression-free Survival Rates at 6 and 12 Months [From Day 1 to documented progression of disease (up to 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
R/M Cohort: Overall Survival Rates at 1, 2, and 3 Years [From Day 1 to date of death by any cause (up to 3 years)]
Overall survival is defined as the time from the first day of study treatment to the date of death by any cause
R/M Cohort: Duration of Response [From Day 1 to documented progression of disease (up to 3 years)]
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
R/M Cohort: Duration of Clinical Benefit [From Day 1 to documented progression of disease (up to 3 years)]
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
R/M Cohort: Complete Response Rate [From Day 1 to documented progression of disease (up to 3 years)]
Percentage of subjects achieving a complete response
R/M Cohort: Disease Control Rate [From Day 1 to documented progression of disease (up to 3 years)]
Percentage of patients achieving complete response, partial response, or stable disease
R/M Cohort: Number of Patients Who Undergo Attempted Definitive Resection [From Day 1 to end of study (up to 3 years)]
Number of Patients Who Undergo Attempted Definitive Resection
R/M Cohort: Frequency, Nature, and Severity of 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]
Percentage of subjects with TEAEs and SAEs

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).