| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Primary or recurrent stage III-IVA cutaneous squamous cell carcinoma of all body sites OR tage I-II cutaneous squamous cell carcinoma, only in the case of:
• Presence of multifocal disease for which extensive and/or mutilating surgery is necessary (e.g. near-total scalp resection).
• Situated in an anatomical localization that necessitates extensive and/or mutilating surgery (e.g. orbital exenteration). |
Primair of recidiverend stadium III-IVa cutaan plaveiselcelcarcinoom op het gehele lichaam
OF
stadium I-II cutaan plaveiselcelcarcinoom in het geval van:
- aanwezigheid van multifocale ziekte waarvoor uitgebreide en of mutilerende chirurgie nodig is (bijvoorbeeld (bijna) gehele scalp resectie).
- aanwezigheid in een anatomische lokalisatie waarbij uitgebreide of mutilerende chirurgie nodig is (orbita exenteratie) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Squamous cell carcinoma of the skin |
| Plaveiselcelcarcinoom van de huid |
|
| 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 | 10041834 |
| E.1.2 | Term | Squamous cell carcinoma of skin |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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.1.2 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10081136 |
| E.1.2 | Term | Skin squamous cell carcinoma recurrent |
| 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 determine the histopathological response rate to neo-adjuvant nivolumab and nivolumab plus ipilimumab at time of SOC (surgery ± RT). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
- To establish whether short-term neo-adjuvant nivolumab w/wo ipilimumab is safe prior to standard of care surgery.
- To compare recurrence free survival (RFS) at 2 years follow-up (FU) for patients responsive and non-responsive to neo-adjuvant ICI;
- To compare overall survival (OS) at 2 years FU for patients responsive and non-responsive to neo-adjuvant ICI
- To assess rate and type of AE (NCI CTCAE v.5.0) up to 2 years FU after SOC
- To assess the response of potentially additional actinic keratosis (AK) to ICI at day 14, day 28 (at time of surgery) and during FU
- To evaluate health related quality of life
Exploratory objectives
- To assess the (ex vivo) kinetics* of local and systemic immunological responses upon nivolumab or nivolumab plus ipilimumab and their correlation with clinical outcome.
- To identify parameters to be exploited for future immunotherapeutic regimens
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 18 years or older.
2. Patient is able to understand and comply with the protocol requirements and has signed the informed consent form.
3. World Health Organization (WHO) Performance Status 0 or 1 (Appendix B).
4. Patients with histologically or cytologically confirmed, primary or recurrent stage III-IVA CSCC of all body sites.
• Primary tumor sites Head and Neck:
o Vermillion border lip: C00.0, C00.1, C00.2
o Skin of lip NOS: C44.0
o External ear: C44.2
o Skin face unspecified (ao: external lip and nasal vestibulum): C44.3
o Skin scalp and neck: C44.4
o Overlapping lesion of skin: C44.8
o Primary site eyelid: C44.1
• CSCC outside head and neck area, but not vulva, anus and penis
OR
Patients with histologically or cytologically proven stage I-II CSCC, only in the case of:
• Presence of multifocal disease for which extensive and/or mutilating surgery is necessary (e.g. near-total scalp resection).
• Situated in an anatomical localization that necessitates extensive and/or mutilating surgery (e.g. orbital exenteration).
5. Eligible for standard-of-care, curatively intended surgery with or without adjuvant radiotherapy.
6. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109 /L, Neutrophils ≥1.5x109 /L, Platelets ≥100 x109 /L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN (except subjects with Gilbert Syndrome, who are eligible when total bilirubin < 3.0 mg/dL).
7. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. They should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of the investigational drug.
8. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) prior to the start of nivolumab or nivolumab + ipilimumab.
9. Men who are sexually active with WOCBP must use a contraceptive method with a failure rate of less than 1% per year and will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Surgically sterile or azoospermic men do not require aforementioned contraception.
|
|
| E.4 | Principal exclusion criteria |
4.3 Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from participation in this study:
1. Distantly metastasized (stadium IVb) CSCC.
2. SCC localized in a mucosal surface (i.e. anus, vulva, penis or mucosal portion of lip).
3. Patients for whom SOC consists of definitive (brachy)radiotherapy.
4. Primary or recurrent CSCC appearing in an area that has been previously irradiated.
5. Prior anti-CTLA4 or anti-PD1 immunotherapy.
6. Active human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
7. A positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C antibody (HCV Ab).
8. Subjects with any active autoimmune disease or a documented history of autoimmune disease, except for:
• Subjects with vitiligo
• Resolved childhood asthma/atopy
• Residual hypothyroidism due to an autoimmune condition requiring only hormone replacement
• Psoriasis not requiring systemic treatment
• Any condition not expected to recur in the absence of an external trigger.
9. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or AE.
10. A concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
11. Pregnant or nursing.
12. A history of allergy to study drug components and/or a history of severe hypersensitivity to any monoclonal antibody.
13. Use of other investigational drugs 30 days before study drug administration and 5 half times before study inclusion.
14. Use of prohibited medication at start of study period.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be histopathological tumor response after neo-adjuvant ICI, defined as the proportion of viable tumor cells left in the resected specimen. Responses will be divided into histopathological complete response (pCR, no viable tumor cells), histopathological near complete response (near-pCR, ≤10% viable tumor cells) and histopathological partial response (pPR, ≤50% viable tumor cells). Pathological responses will be compared to responses assessed via clinical examination and imaging studies (FDG-PET and (functional)MRI) by RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Rate and type of AE (NCI CTCAE v 5.0) prior to standard of care, and no significant delay (>1 week) or cancelation of SOC surgery due to immune-related toxicity.
- RFS at 2 years FU of responders versus non-responders to neo-adjuvant ICI
- OS at 2 years FU of responders versus non-responders to neo-adjuvant ICI
- Rate and type of AE (NCI CTCAE v 5.0) up to 2 years FU after SOC
- Clinical response of potentially additional AK surface areas after ICI identified by digital clinical photography on day 0, day 14, day 28 and during FU.
- Quality of life as measured by EORTC QLQ-C30, H&N 35, EQ5D, CWS, IT questionnaire and the sexuality questionnaire
Exploring the TME (early) upon ICI:
- IHC and Bulk DNA & RNA sequencing of local tumor (when feasible also lymph node metastases) specimens at the aforementioned time points before and after start of ICI*, and its correlation to clinical outcome.
- The development of an ex vivo functional assay for CSCC (Daniela Thommen platform) to predict individual ICI response.
- The development of an ex vivo functional assay to challenge tumor specimens (and when feasible lymph node specimens) with ICI drugs at aforementioned time-points before and after start of neoadjuvant ICI*.
- Single cell sequencing of tumor specimens before and after start of ICI*.
- Hyperion Mass Cytometry of tumor specimens (and when feasible lymph node specimens) before and after start of ICI*.
Endpoints for exploring systemic immunotherapy-related alterations:
- Fresh blood flow cytometry (with a focus on suppressive cells as monocytes, neu-trophils) will be performed pre-, on and post-treatment* on all blood samples.
- Heparin peripheral blood mononuclear cells (PBMCs) will be analysed pre-, on and post-treatment* on all blood samples for a quantitative and qualitative assessment of circulating adaptive immune cells.
- Serum blood will be analysed for chemokines and cytokines, pre-, on and post-treatment* on all blood samples.
- EDTA blood will be analysed complement factors, pre-, on and post-treatment* on all blood samples.
- T-cell receptor sequencing of baseline TILs and their potential expansion in the pe-ripheral blood compartment on-treatment (‘immunoSeq’.).
- EDTA blood will be analysed for ctDNA (kinetics) before treatment, on treatment, and long-term after neo-adjuvant ICI*.
*= before treatment, and one week (either day 2-3, or day 4-6 or day 7-9, at least 6 people per treatment arm), two weeks (right before 2nd infusion of immunotherapy), 4 weeks (at time of surgery) and long-term after start of ICI, see figure 1 and 2, and table 1, pages (23, 24 and 47).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Described at secondary endpoints. (2 years after treatment for OS and RFS).
|
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| 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 | 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| LVLS is the end of the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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