| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Cutaneous Squamous Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077314 |
| E.1.2 | Term | Skin squamous cell carcinoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 nodal or distant metastatic CSCC as assessed by complete response rate (CRR) and overall response rate (ORR) according to blinded independent review. |
|
| E.2.2 | Secondary objectives of the trial |
•To estimate the treatment effect on progression-free survival (PFS) by blinded independent review (BIR)
•To estimate ORR/ CRR according to investigator review
• To estimate ORR/CRR for patients with metastatic (nodal or distant) CSCC according to investigator and BIR
• To estimate ORR/ CRR for patients with locally advanced CSCC according to investigator and BIR
• To estimate ORR/ CRR for patients having previously received systemic
CSCC-directed therapy according to investigator and BIR
• To estimate ORR/ CRR for patients not having previously received systemic CSCC-directed therapy according to investigator and BIR
• To estimate the duration of response (DOR) according to investigator and BIR
• To estimate overall survival
• To estimate 3 year survival
• To assess the effects of cemiplimab and cemiplimab combined with RP1 on the changes in scores of patient-reported outcomes (EORTC QLQ-C30.
• To assess the safety and tolerability of cemiplimab alone and combined with RP1 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Voluntary agreement to provide written informed consent and willingness and ability to comply with protocol requirements.
2. 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.
3. At least 1 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 the aggregate of ≥ 1 cm at baseline.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Appendix 4).
5. Male or female ≥18 years old.
6. Hepatic function:
a. Total bilirubin ≤1.5 x upper limit of normal (ULN); (if liver metastases ≤3 x ULN). Patients with Gilbert's Disease and total bilirubin up to 3 x ULN may be eligible after communication with and approval from the medical monitor.
b. Transaminases (ALT or AST) ≤3 x ULN (or ≤5.0 x 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 x but ≤5 x ULN, total bilirubin must be ≤1.5 x ULN. If total bilirubin is >1.5 x but ≤3 x ULN, both transaminases (AST and ALT) must be ≤3 x ULN.
7. Renal function: Serum creatinine ≤1.5 x ULN or, If serum creatinine >1.5xULN, calculated creatinine clearance ≥30mL/min (using Cockcroft).
8. Bone marrow function:
a. Hemoglobin ≥9.0 g/dL
b. Absolute neutrophil count (ANC) ≥1.5 x 109/L
c. Platelet count ≥100 x 109/L
9. Prothrombin time (PT) ≤ 1.5 x ULN (or international normalization ratio [INR] ≤ 1.3) and partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN.
10. Anticipated life expectancy >12 weeks.
11. 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 effect contraceptive methods and instructions of patients and partners, see Section 9.3.4.9.
12. Locally advanced CSCC only (Surgery): 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 multi-disciplinary disease management team, or documented to have refused surgery.
13. Locally advanced CSCC only (Radiotherapy): Patients must be deemed as not appropriate candidates for curative radiation therapy, or documented to have refused surgery despite consultation.
This must include the opinion of either a radiation oncologist, a medical
oncologist, a head and neck surgeon, a dermatologist with expertise in
cutaneous malignancies, or a multidisciplinary team.
14. 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 and biomarker analyses.
15. Tumor biopsies will be taken as specified in the Schedules of Events (Section 9.1). |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with an oncolytic therapy.
2. Patients with active significant herpetic infections or prior complications of HSV-1 infection (e.g. herpetic keratitis or encephalitis or disseminated herpes infection).
3. Patients who require intermittent or chronic use of systemic (oral or IV) anti-virals with known anti-herpetic activity (e.g. acyclovir).
4. 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 has 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, or psoriasis that does not require systemic treatment.
5. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway.
6. Prior treatment with other immune modulating agents other than as adjuvant or neoadjuvant therapy within 3 years. Examples of immune modulating agents include therapeutic anti-cancer vaccines, cytokine treatments (other than G-CSF or erythropoietin), or agents that target CTLA-4, 4-1BB (CD137), PI 3-K-delta, or OX-40.
7. Untreated brain metastasis(es) that may be considered active.
8. Immunosuppressive corticosteroid doses (> 10 mg prednisone daily or equivalent) within 2 weeks prior to randomisation/enrolment.
9. 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) or HIV infection.
10. Active infection requiring systemic therapy within 14 days prior to randomisation/enrolment.
11. History of interstitial lung disease (ILD)/pneumonitis within the last 5 years or a history of ILD/pneumonitis requiring treatment with systemic steroids.
12. 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 randomisation.
13. Grade ≥ 3 hypercalcemia at time of enrollment.
14. Any systemic anticancer treatment (chemotherapy, targeted systemic therapy, photodynamic therapy), investigational or standard of care, within 28 days of randomisation/enrolment or planned to occur during the study period (patients receiving bisphosphonates or denosumab are not excluded). Radiation therapy within 14 days of randomisation/enrolment 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/enrolment.
15. Was administered a live vaccine ≤ 28 days before randomisation.
16. History of documented allergic reactions or acute hypersensitivity reaction attributed to antibody treatments.
17. Patients with allergy or hypersensitivity to RP1 or cemiplimab's excipients must be excluded.
18. Female who has a positive serum β-hCG pregnancy (at screening ≤72 hours prior to first study treatment) and urine pregnancy test (Cycle 1 Day 1) or is breast feeding or planning to become pregnant.
19. 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. of the study protocol.
20. 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.
21. 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.
22. Inability to undergo any contrast-enhanced radiologic response
assessment.
23. 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 randomisation/enrolment. See exclusion criteria in the protocol for exceptions. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoints for this study are ORR and CRR according to blinded independent review:
• ORR/ CRR will be determined using modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as specified in Appendix 1 for radiologically accessible lesions and clinical and composite response criteria as specified in Appendix 2 for clinically accessible lesions. These criteria include that PD must be confirmed by documentation of further progression ≥ 4 weeks following the initial documentation of objective response or PD.
• In patients suspected of achieving a CR by clinical assessment, tumor biopsies may be used in the final determination of CR.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients should be re-evaluated for response every 9 weeks from randomisation. Confirmatory scans should also be obtained ≥ 4 weeks following initial documentation of objective response or progressive disease. |
|
| E.5.2 | Secondary end point(s) |
The secondary outcome measure is PFS by blinded independent review. Other secondary efficacy outcome measures are:
• ORR/ CRR by investigator review
• ORR/ CRR for patients with metastatic (nodal or distant) disease by investigator and blinded independent review
• ORR/ CRR for patients with locally advanced disease by investigator and blinded independent review
• ORR/ CRR for patients having previously received systemic CSCC-directed therapy by investigator and blinded independent review
• ORR/ CRR for patients not having previously received systemic CSCC-directed therapy by investigator and blinded independent review
• PFS by investigator review
• DOR by investigator and blinded independent review: DOR is for responders only and defined as the length of time from the date of 1st documented response to the date of initial disease progression or death. For those patients who did not have disease progression or death, DOR is calculated from the date of 1st documented response to the date of the last valid disease assessment (before any subsequence anti-cancer therapy) and will be censored.
• OS (OS will be calculated for the ITT population and is defined as the length of time from the date of randomization to the date of death. For those patients who remain alive at the time of the data cut-off or those who discontinued for reasons other than death, OS is calculated from the
date of randomization to the last date they are known to be alive and will be censored on that date.)
• 3-year survival
• Change in scores of patient-reported outcomes on EORTC QLQ-C30
• Safety and tolerability of cemiplimab alone and combined with RP1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients should be re-evaluated for response every 9 weeks from the date of randomisation. Confirmatory scans should also be obtained ≥ 4 weeks following initial documentation of objective response or progressive disease. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| France |
| Germany |
| Greece |
| Poland |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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