Squamous Cell Carcinoma of Head and Neck, Locally Advanced Head and Neck Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma
Conditions
Keywords
Squamous cell carcinomas of head and neck, Immunotherapy, Immuno-oncology, Oncolytic virus, Oncolytic immuno-gene therapy
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.
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
Interventions
BIOLOGICALRP3
Genetically modified herpes simplex type 1 virus
OTHERCCRT(concurrent chemoradiation therapy)
CCRT consisting of intensity modulated radiation therapy combined with a cis-platinum
chemotherapeutic agents
BIOLOGICALnivolumab
anti-PD1 monoclonal antibody
Sponsors
Replimune Inc.
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Countries
Czechia, France, Germany, Greece, Poland, Spain, United Kingdom, United States
Outcome results
None listed