Phase 2 Randomized Controlled Study of Cemiplimab Monotherapy and Cemiplimab Plus Vusolimogene Oderparepvec in Advanced Cutaneous Squamous Cell Carcinoma
- Trial ID
- 2024-512652-38-00
- Protocol
- RPL-002-18
- Sponsor
- Replimune Group Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to estimate the clinical benefit of **cemiplimab** monotherapy versus cemiplimab in combination with RP1 for patients with locally advanced or nodal or distant metastatic **cutaneous squamous cell carcinoma** (CSCC). This is assessed by overall response rate (ORR) and complete response rate (CRR) according to blinded independent review. Evaluating these response rates is clinically relevant as it provides insight into the efficacy of the treatment regimens in managing advanced CSCC, potentially guiding therapeutic decisions and improving patient outcomes.
Secondary objectives include:
- Estimating the treatment effect on progression-free survival (PFS) according to blinded independent review.
- Estimating ORR/CRR according to investigator review.
- Estimating ORR/CRR for patients with metastatic (nodal or distant) CSCC according to investigator and blinded independent review.
- Estimating ORR/CRR for patients with locally advanced CSCC according to investigator and blinded independent review.
- Estimating ORR/CRR for patients having previously received systemic CSCC-directed therapy according to investigator and blinded independent review.
- Estimating ORR/CRR for patients not having previously received systemic CSCC-directed therapy according to investigator and blinded independent review.
- Estimating the duration of response (DOR) according to investigator and blinded independent review.
- Estimating progression-free survival (PFS) according to investigator review.
- Estimating overall survival (OS).
- Estimating 3-year survival.
- Assessing the effects of cemiplimab and cemiplimab combined with RP1 on the changes in scores of patient-reported outcomes on quality of life using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).
- Assessing the safety and tolerability of cemiplimab alone and combined with RP1.
Participants
The clinical trial involves a total of **86 participants** diagnosed with **cutaneous squamous cell carcinoma** (CSCC). The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their diagnosis of locally advanced or metastatic CSCC, with a requirement for a histologically confirmed diagnosis. The trial does not include a vulnerable population. Participants are required to have an **ECOG performance status** of 1 or less, although those with a status of 2 may be considered if it is solely due to CSCC. The trial population was chosen to ensure that participants have adequate hepatic and bone marrow function, as well as a life expectancy of more than 12 weeks. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Participants must agree to use highly effective contraception methods during and after the study period. The trial excludes individuals who are candidates for curative surgery or radiotherapy, unless they have refused such treatments. The study aims to evaluate the clinical benefit of cemiplimab monotherapy versus its combination with RP1, focusing on overall and complete response rates.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled, open-label, Phase 2 study to evaluate the efficacy of **cemiplimab** as a monotherapy and in combination with **vusolimogene oderparepvec** in patients with advanced **cutaneous squamous cell carcinoma** (CSCC). The primary objective is to estimate the clinical benefit of these treatments by assessing the overall response rate (ORR) and complete response rate (CRR) through blinded independent review. The trial is expected to run from May 18, 2021, to August 15, 2025, with an estimated duration of participant involvement of up to 108 weeks for those receiving cemiplimab and up to 24 weeks for those receiving the combination therapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and hepatic function. Following successful screening, participants will be randomized to receive either cemiplimab alone or in combination with vusolimogene oderparepvec. The study includes regular follow-up visits to monitor treatment response and safety, with assessments conducted using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Early termination from the study may occur if participants experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial will also assess secondary endpoints, including progression-free survival (PFS), duration of response (DOR), and overall survival (OS), alongside safety and tolerability evaluations. Participants are required to adhere to protocol requirements, including the provision of tumor biopsies for central pathology review and biomarker analysis. The study aims to provide valuable insights into the treatment of advanced CSCC, contributing to the development of effective therapeutic strategies.
Treatment
The clinical trial involves the administration of **LIBTAYO** (cemiplimab), a **concentrate for solution for infusion**. Cemiplimab is a monoclonal antibody classified under the ATC code L01XC33. It is administered via **intravenous infusion**. The maximum daily dose is 350 mg, with a total maximum dose of 12,600 mg over a treatment period of up to 108 weeks. The product is manufactured by Regeneron Ireland D.A.C. and is not a pediatric formulation. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
Another investigational product used in the trial is **Vusolimogene oderparepvec**, also known by its sponsor product code RP1. This is a **solution for injection** intended for **intratumoral use**. The active substance is a genetically modified herpes simplex virus type 1, designed to express granulocyte-macrophage colony-stimulating factor and a fusogenic glycoprotein. The maximum daily dose is 10,000,000 plaque-forming units (PFU) per milliliter, with a total maximum dose of 160,000,000 PFU over a treatment period of up to 24 weeks. This product is developed by Replimune, Ltd. and is also not a pediatric formulation. The administration is carefully monitored to ensure accurate dosing and participant compliance.
Efficacy
The efficacy of the clinical trial will be assessed using the primary endpoints of Overall Response Rate (ORR) and Complete Response Rate (CRR) as determined by a blinded independent review. These endpoints will be evaluated using the modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for radiologically assessable lesions and clinical and composite response criteria for clinically assessable lesions. Confirmatory scans are required at least four weeks following the initial documentation of an objective response or progressive disease. In cases where a complete response is suspected based on clinical assessment, tumor biopsies may be utilized for the final determination of a complete response.
Secondary efficacy endpoints include Progression-Free Survival (PFS) by blinded independent review, ORR/CRR by investigator review, and ORR/CRR for patients with metastatic or locally advanced disease by both investigator and blinded independent review. Additional secondary endpoints involve Duration of Response (DOR) by investigator and blinded independent review, PFS by investigator review, Overall Survival (OS), and 3-year survival rates. Patient-reported outcomes will be measured using changes in scores on the EORTC QLQ-C30. The safety and tolerability of **cemiplimab** alone and in combination with RP1 will also be assessed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Voluntary agreement to provide written informed consent and willingness and ability to comply with protocol requirements.
- Anticipated life expectancy > 12 weeks.
- Female and male patients of reproductive potential must agree to avoid becoming pregnant or impregnating a partner and adhere to highly effective contraception methods for 6 months after the last dose of cemiplimab or cemiplimab and RP1 combination treatment. In addition, male patients must refrain from donating sperm during this study treatment and for up to 6 months after the last dose of cemiplimab or cemiplimab and RP1 combination treatment. For a definition of highly effective contraceptive methods and instructions of patients and partners, see Section 9.3.4.9
- Locally advanced CSCC only (Surgery): Patients must be deemed as not appropriate candidates for curative surgery in the opinion of either a medical oncologist with experience in cutaneous malignancy management, a dermatologist, a head and neck surgeon, or a multidisciplinary disease management team, or documented to have refused surgery. See Section 4.2.1 of the protocol for definitions of acceptable contraindications for surgery.
- Locally advanced CSCC only (Radiotherapy): Patients must be deemed as not appropriate candidates for curative radiation therapy as defined in the inclusion section of the protocol, or documented as having refused radiotherapy despite consultation. This must include either a radiation oncologist, a medical oncologist, a head and neck surgeon, a dermatologist with expertise in cutaneous malignancies, or a multidisciplinary team. See Section 4.2.1 of the protocol for definitions of acceptable contraindications for radiation therapy.
- All patients must consent to provide archived (within 12 months [6 months preferred] of screening date) or newly obtained tumor material (either formalin-fixed, paraffin-embedded [FFPE] block or unstained slides) for central pathology review for confirmation of diagnosis of CSCC and biomarker analysis.
- Tumor biopsies will be taken as specified in the Schedules of Events (Section 9.1).
- Histologically confirmed diagnosis of locally advanced or metastatic (nodal or distant) CSCC by local pathology report. Metastatic (nodal or distant) disease is defined as disseminated disease distant to the initial/primary site of diagnosis. The locally recurrent disease is defined as previously treated disease (with either surgery, radiotherapy, or systemic therapy) and is not amenable to either curative surgery, radiotherapy, or concurrent chemoradiotherapy treatment.
- At least one measurable lesion and lesion(s) that are injectable, which individually or in aggregate meet the measurable criteria. There is no minimum tumor size for injection, provided there are injectable tumors that are in aggregate ≥1 cm at baseline. Note on measurable lesions: A lesion in an area that has received prior locoregional therapy, including previous radiotherapy, is not considered measurable unless there has been demonstrated progression in the lesion since the therapy as defined by RECIST 1.1 (Appendix 1) or clinical assessment criteria (Appendix 2). Note on Metastatic (nodal or distant) CSCC: Measurable lesions are lesions ≥1.0 cm in their longest diameter (≥1.5 cm shortest diameter for lymph nodes) according to RECIST 1.1. Patients with metastatic disease that does not meet target lesion criteria by RECIST 1.1 (eg, bone only lesions, perineural disease) and with externally visible CSCC target lesion(s) may be enrolled if they have at least 1 measurable externally visible lesion ≥1.0 cm in both perpendicular diameters at baseline. Composite response criteria (Appendix 2) should be used to evaluate patients who have both externally visible target lesion(s) that are evaluable by clinical response criteria (Appendix 2) and non-measurable lesions by RECIST 1.1 (Appendix 1) that are being followed radiologically as non-target lesions. Note on locally advanced CSCC: Measurable lesions are lesions ≥1.0 cm in both perpendicular diameters that are being evaluated by clinical response criteria (Appendix 2).
- ECOG performance status (PS) ≤1 (Appendix 4). Note: Patients with ECOG PS 2 at baseline may be allowed to enroll if PS 2 status is only related to the disease under study (ie, CSCC), and they fulfill all other eligibility criteria, and upon consultation with the medical monitor.
- Male or female ≥18 years old.
- Hepatic function: a. Total bilirubin ≤1.5 × upper limit of normal (ULN); (if liver metastases ≤3 × ULN). Patients with Gilbert’s Disease and total bilirubin up to 3 × ULN may be eligible after communication with and approval from the medical monitor b. Transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) ≤3 × ULN (or ≤5.0 × ULN, if liver metastases) c. Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN, if liver or bone metastases) Note for patients with hepatic metastases who wish to enroll: If transaminase levels (AST and/or ALT) are >3 × but ≤5 × ULN, total bilirubin must be ≤1.5 × ULN. If total bilirubin is >1.5 × but ≤3 × ULN, both transaminases (AST and ALT) must be ≤3 × ULN.
- Νεφρική λειτουργία: Κρεατινίνη ορού ≤1,5 × ΑΦΤ Ή, εάν η κρεατινίνη ορού > 1,5 × ΑΦΤ, υπολογιζόμενη κάθαρση κρεατινίνης ≥ 30 mL/min (με Cockcroft).
- Bone marrow function: a. Hemoglobin ≥9.0 g/dL b. Absolute neutrophil count (ANC) ≥1.5 × 109/L c. Platelet count ≥100 × 109/L
- Prothrombin time (PT) ≤1.5 × ULN (or international normalized ratio [INR] ≤ 1.3) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN. See additional criteria for patients on chronic anticoagulation in the inclusion criteria section of the protocol.
Exclusion Criteria
- Prior treatment with an oncolytic therapy.
- Active infection requiring systemic therapy within 14 days prior to randomization/enrollment.
- History of interstitial lung disease (ILD)/pneumonitis within the last 5 years or a history of ILD/pneumonitis requiring treatment with systemic steroids.
- History of myocarditis or congestive heart failure (as defined by the New York Heart Association Functional Classification III or IV), or unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection or myocardial infarction within 6 months of randomization.
- Grade ≥3 hypercalcemia at time of enrollme
- Any systemic anticancer treatment (chemotherapy, targeted systemic therapy, or photodynamic therapy), investigational or standard of care, within 28 days of randomization/enrollment or planned to occur during the study period (patients receiving bisphosphonates or denosumab are not excluded). Radiation therapy within 14 days of randomization/enrollment or planned to occur during the study period. Any major surgical procedure ≤28 days before randomization. Patients must have recovered adequately from the toxicity and/or complications from prior interventions prior to randomization/enrollment.
- Was administered a live vaccine ≤28 days before randomization. Note: Seasonal vaccines for influenza or SARS-CoV-2 are generally inactivated vaccines and are allowed (Please see Section 8.1 for additional guidance). Vaccines that are live/attenuated vaccines (such as the intranasal influenza vaccine) are not allowed
- Patients with active significant herpetic infections or prior complications of HSV-1 infection (eg, herpetic keratitis, encephalitis, or disseminated herpes infection). Note: patients with sporadic cold sores l may be enrolled as long as no active cold sores are present at the time of randomization/enrollment. See Section 5.5 for further guidance
- Patients who require intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).
- Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for ImAEs or a diagnosis of immunodeficiency disorders (such as human immunodeficiency virus [HIV] disease or organ transplantation or hematologic malignancies associated with immune suppression). Note: The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that required only hormone replacement, alopecia areata or psoriasis that does not require systemic treatment.
- Prior treatment with an agent that blocks the programmed cell death-1 (receptor) (PD-1)/PD-L1 pathway
- Prior treatment with other immune modulating agents other than as adjuvant or neoadjuvant therapy within 3 years. Examples of immune modulating agents include therapeutic anticancer vaccines, cytokine treatments (other than granulocyte colony-stimulating factor [G-CSF] or erythropoietin), or agents that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), 4-1BB (CD137), PI 3-K-delta, or OX-40.
- Untreated brain metastasis(es) that are considered active. See exclusion criteria in the protocol for exceptions for brain metastases (Section 4.2.2).
- Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 2 weeks prior to randomization/enrollment. See exclusion criteria in protocol for exceptions for corticosteroids (Section 4.2.2).
- Patient who has acute or chronic active hepatitis B or known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or hepatitis C virus (defined as HCV RNA [qualitative] or HIV infection. Note: No testing for Hepatitis B, Hepatitis C, or HIV is required unless mandated by local health authority or clinically indicated.
- History of documented allergic reactions or acute hypersensitivity reaction attributed to antibody treatments.
- Patients with allergy or hypersensitivity to RP1’s or cemiplimab’s excipients must be excluded.
- Female who has a positive serum β-hCG pregnancy (at screening within 72 hours before dosing) and urine pregnancy test (Cycle 1 Day1) or is breast feeding or planning to become pregnant.
- Concurrent malignancy other than CSCC and/or history of malignancy other than CSCC within 3 years of date of first planned dose of cemiplimab, except for tumors with negligible risk of metastasis or death. Examples are provided in Section 4.2.2.
- Any acute or chronic psychiatric problems or substance abuse disorders that, in the opinion of the investigator, would interfere with the patient cooperating with the requirements of the study.
- Any medical co-morbidity, physical examination finding, or metabolic dysfunction, or clinical laboratory abnormality that, in the opinion of the investigator, renders the patient unsuitable for participation in a clinical trial due to high safety risks and/or potential to affect interpretation of results of the study.
- Inability to undergo any contrast-enhanced radiologic response assessment (except as outlined in the protocol eligibility exclusion section [Section 4.2.2]).
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization/enrollment. See exclusion criteria in the protocol for exceptions (Section 4.2.2).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 18 May 2021 | 6 |
 France | Not Recruiting | 18 May 2021 | 59 |
 Germany | Not Recruiting | 18 May 2021 | 9 |
 Greece | Not Recruiting | 18 May 2021 | 33 |
 Poland | Not Recruiting | 18 May 2021 | 22 |
 Spain | Not Recruiting | 18 May 2021 | 14 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Vusolimogene oderparepvec | Test | SOLUTION FOR INJECTION | INTRATUMORAL USE | 10000000 | 24 | PRD4949048 |
Vusolimogene oderparepvec | Test | SOLUTION FOR INJECTION | INTRATUMORAL USE | 10000000 | 24 | PRD7532419 |
LIBTAYO 350 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 350 | 108 | PRD7478447 |
LIBTAYO 350 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 350 | 108 | PRD7514334 |
LIBTAYO 350 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 350 | 108 | PRD7514333 |
Vusolimogene oderparepvec | Test | SOLUTION FOR INJECTION | INTRATUMORAL USE | 10000000 | 24 | PRD7532420 |
Vusolimogene oderparepvec | Test | SOLUTION FOR INJECTION | INTRATUMORAL USE | 10000000 | 24 | PRD4949047 |
Vusolimogene oderparepvec | Test | SOLUTION FOR INJECTION | INTRATUMORAL USE | 10000000 | 24 | PRD4949046 |