| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Resectable high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| High-risk Locally Advanced cutaneous squamous cell carcinoma (non-melanoma skin cancer) |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041823 |
| E.1.2 | Term | Squamous cell carcinoma |
| 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 |
| To compare the recurrence-free survival (RFS), as assessed by the investigator and confirmed by biopsy, in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare overall survival (OS) in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy
2. To compare mean change from baseline in health-related quality of life (HRQoL) scores from the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ)-C30, in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy
3. To determine the safety and tolerability of pembrolizumab as adjuvant therapy
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (Blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time |
|
| E.3 | Principal inclusion criteria |
1. Participants must have histologically confirmed cSCC as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted)
2. Participant must have undergone complete macroscopic resection of all known cSCC disease with or without microscopic positive margins. For those participants with residual microscopic positive margin involvement, confirmation that additional re-excision is not possible must be provided. Surgery may consist of 1 or a combination of the following:
a. Resection of the primary lesion
b. Any type of neck dissection(s)
c. Any type of parotidectomy (superficial, total, partial)
3. Participant must have histologically confirmed LA cSCC with a high-risk feature(s) as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted).
High-risk features include at least 1 of the following:
a) Histologically involved nodal disease with the following features:
• Extracapsular extension with either at least 1 lymph node >2 cm in greatest diameter or ≥2 lymph nodes involved.
b) Any index tumor with ≥2 of the following high-risk features:
• Tumor ≥4 cm with a depth >6 mm or invasion of subcutaneous fat
• Multi-focal perineural invasion for nerves of <0.1 mm diameter (3 or more foci) or any involved nerve ≥0.1 mm diameter
• Poor differentiation and/or sarcomatoid and/or spindle cell histology
• Recurrent disease (any cSCC that recurs within 3 years in the previously surgically or topically treated area)
• Satellite lesions (satellitosis) and/or in-transit metastases
c) Any gross cortical bone invasion or skull base invasion and/or skull base foramen invasion.
4. Participant must have completed adjuvant RT for LA cSCC with last dose of RT ≥4 weeks and ≤16 weeks from randomization
5. Participant must have completed at least 45 Gy of adjuvant RT for LA cSCC prior to study entry
6. Participant is disease-free as assessed by the investigator with complete radiographic staging assessment ≤28 days from randomization
7. Participant is male or female and at least 18 years of age at the time of signing the informed consent
8. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP)
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis),during the intervention period and for at least 120 days after the last dose of study intervention The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
- A WOCBP must have a negative highly sensitive pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
9. Participant (or legally acceptable representative, if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research
10. Participant provides a tumor tissue sample adequate for PD-L1 testing as determined by central laboratory testing. This tissue sample may be obtained from either the surgical resection, or a prior archival tissue specimen not previously irradiated. FFPE tissue blocks are preferred to slides.
11. Participant has a life expectancy of greater than 3 months.
12. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days prior to treatment initiation.
13. Participant has adequate organ function.Specimens must be collected within 10 days prior to the start of study treatment
|
|
| E.4 | Principal exclusion criteria |
1. Has macroscopic residual cSCC after surgery and/or recurrence with active cSCC disease before randomization
2. Has any other histologic type of skin cancer other than invasive cSCC, eg, basal cell carcinoma that has not been definitively treated with surgery or radiation, Bowen’s disease, MCC, melanoma
3. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another costimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
5. Has received prior systemic anticancer therapy including investigational agents for cSCC within 4 weeks prior to randomization
6. Participant must have recovered from all radiation-related toxicities, and not have had radiation pneumonitis
7. Has received a live vaccine within 30 days prior to the first dose of study treatment.Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
8. 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 the first dose of study treatment
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
10. Has a diagnosed and/or treated additional malignancy within the past 5 years prior to randomization
11. Has known active central nervous system metastases and/or carcinomatous meningitis
12. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
13. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
14. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
15. Has an active infection requiring systemic therapy
16. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
17. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV; defined as HCV RNA [qualitative] is detected) infection
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
19. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
20. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
21. Has had an allogeneic tissue/solid organ transplant
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Recurrence-free survival (RFS) as assessed by the investigator and confirmed by biopsy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 60 months |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS)
2. Change from baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
3. Change From Baseline in Physical Functioning Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1-5 Score
4. Percentage of participants who experience an adverse event (AE)
5. Percentage of participants who discontinue study treatment due to an adverse event (AE)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 60 months
2. Baseline and up to approximately 60 months
3. Baseline and up to approximately 60 months
4. Up to approximately 63 months
5. Up to approximately 38 months |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Colombia |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Mexico |
| Norway |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| United Kingdom |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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