Towards Cure Via Only Ultra-short ICB in CSCC

Phase 2

Not yet recruiting

• Conditions: Cutaneous Squamous Cell Carcinoma (CSCC); Cutaneous Squamous Cell Cancer; Cutaneous Squamous Cell Carcinoma of the Head and Neck; Cutaneous Squamous Cell Carcinoma
• Interventions: Drug: Nivolumab; Drug: Ipilumimab

• Registration Number: NCT06823479
• Lead Sponsor: The Netherlands Cancer Institute

Brief Summary

The goal of this clinical trial is to determine whether cutaneous squamous cell carcinoma patients can be cured using only immunotherapy, without surgery or radiotherapy.

Detailed Description

This is an investigator-initiated phase 2 clinical trial consisting of 41 patients with stage I-IVa CSCC and an indication for morbid/extensive curative surgery. All patients will receive two courses of nivolumab 3 mg/kg in week 0 and week 2, and one course of ipilimumab 1 mg/kg in week 0. In week 5 response to immunotherapy will be evaluated using clinical examination, \[18F\]FDG-PET/CT imaging, regional lymph node ultrasound with FNAC (if applicable) and a multicentre multidisciplinary meeting. Non-responders will receive standard of care surgery (w/wo radiotherapy). Responders will enter a wait-and-monitor follow-up schedule in which response will be monitored every 3 months for a total of 2 years. If a patient is no longer responding to immunotherapy during follow-up they will receive standard of care surgery (w/wo radiotherapy).

Study Timeline

• Study First Submitted: 2025-01-07
• Status Verified: 2025-02
• Study Start: 2025-02
• Study First Submitted QC: 2025-02-06
• Last Update Submitted: 2025-02-06
• Study First Posted: 2025-02-12
• Last Update Posted: 2025-02-12
• Primary Completion: 2029-02
• Study Completion: 2029-02

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 41

Inclusion Criteria

• 18 years of age or older
• UV-related stage I to IVa CSCC with an indication for extensive or disfiguring surgery
• Stage III-IVa CSCC (T3-4N0-3M0 or T0N1-3M0) or multi-focal stage I-II CSCC
• Primary tumour site: vermillion border lip (C00.0, C00.1, C00.2), skin of lip NOS (C44.0), external ear (C44.2), skin face unspecified (ao: external lip and vestibulum nasi) (C44.3), skin scalp and neck (C44.4), overlapping lesion of skin (C44.8), primary site eyelid (C44.1), other body sites: CSCC outside head and neck area, but not vulva, anus or penis.
• World Health Organisation (WHO) performance status of 0-2
• Indication for SOC surgery with curative intent ± RT
• Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109 /L, Platelets ≥100 x109 /L, Haemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x upper limit of normal (ULN), AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN (except patients with Gilbert Syndrome, who are eligible when total bilirubin < 3.0 mg/dL).
• Women of child-bearing 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 time for nivolumab to undergo five x T1/2) after the last dose of the IMP.
• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) prior to the start of ICB.
• Patients willing and able to understand the Dutch study information and protocol requirements and comply with the treatment/intervention schedule, scheduled visits, and other requirements of the study.

Exclusion Criteria

• Distantly metastasized (stadium IVb) CSCC
• SCC localized in a mucosal surface (i.e. anus, vulva, penis or mucosal portion of lip)
• Patients for whom standard of care treatment consists of definitive (brachy)radiotherapy
• Primary or recurrent CSCC appearing in an area that has been previously irradiated
• Prior systemic therapy or immunotherapy.
• Active human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C antibody (HCV Ab)
• Subjects with any active autoimmune disease or a documented history of autoimmune disease, except: 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.
• Underlying medical conditions that, in the investigator's opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity or AEs
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids (up to 5 mg of prednisone per day is allowed)
• Patients who are pregnant or breastfeeding
• History of allergy to study drug components and/or history of severe hypersensitivity to any monoclonal antibody
• Use of other investigational drugs 30 days before study drug administration and 5 half times before study inclusion.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Neoadjuvant nivolumab + ipilimumab	Nivolumab	Intravenous neoadjuvant nivolumab 3 mg/kg in week 0 and 2 in combination with intravenous neoadjuvant ipilimumab 1 m/kg in week 0.
Neoadjuvant nivolumab + ipilimumab	Ipilumimab	Intravenous neoadjuvant nivolumab 3 mg/kg in week 0 and 2 in combination with intravenous neoadjuvant ipilimumab 1 m/kg in week 0.

Primary Outcome Measures

Name	Time	Method
Rate of clinical complete remission after only immunotherapy	From the start of immunotherapy until 24 months of follow-up	The rate of patients with a clinical complete remission at 24 months of follow-up or at time of death prior to 24 months follow-up, whichever comes first, after only immunotherapy, without surgery, radiotherapy or maintenance immunotherapy.

Secondary Outcome Measures

Name	Time	Method
Rate of clinical complete remission after only immunotherapy	From the start of immunotherapy until 12 and 18 months of follow-up.	The rate of patients with a clinical complete remission at 12 and 18 months of follow-up or at time of death prior to the specified time-point, whichever comes first, after only immunotherapy, without surgery, radiotherapy or maintenance immunotherapy
Treatment stops	From the start of immunotherapy until the end of treatment (average 6 weeks)	The amount of times and the length of time the immunotherapy, surgery or adjuvant radiotherapy had to be stopped.
Healthcare consumption	From the start of immunotherapy until 24 months of follow-up.	Healthcare consumption during the trial.
Cost-effectiveness	From the start of immunotherapy until 24 months of follow-up.	The incremental cost-effectiveness ratio between quality-adjusted life years and the cost of trial-related healthcare.
Immune-related adverse events	From the start of immunotherapy until 100 days after the last course of immunotherapy.	The rate and type of immune-related adverse events (CTCAE v5.0, Clavien-Dindo).
Health-related quality of life (IT)	From the start of immunotherapy until 24 months of follow-up.	Immunotherapy questionnaire. Rated on a Likert-type scale from one (never) to four (almost always), to evaluate toxicity after immunotherapy treatment.
Health-related quality of life (sexuality questionnaire)	From the start of immunotherapy until 24 months of follow-up.	Rated on a Likert-type scale from one (never) to four (almost always), to evaluate problems in sexual functioning.
Recurrence-free survival	From the start of immunotherapy until 2 years follow-up.	The length of time a patient survives without recurrent disease.
Health-related quality of life (EORTC QLQ-C30)	From the start of immunotherapy until 24 months of follow-up.	EORTC Core Quality of Life questionnaire. Rated on a Likert-type scale from one (never) to four (almost always), to evaluate different domains. Functional and global health status scales indicated towards better levels of functioning, whereas higher scores in the symptom scales demonstrated higher levels of symptoms.
Treatment duration	From the start of immunotherapy until the end of treatment (average 6 weeks)	Total duration of received treatment
Event-free survival	From the start of immunotherapy until 2 years follow-up.	The length of time a patient survives without recurrent disease or death of any cause.
Health-related quality of life (EORTC QLQ-H&N35)	From the start of immunotherapy until 24 months of follow-up.	EORTC Head and Neck Cancer Quality of Life Questionnaire. Rated on a Likert-type scale from one (never) to four (almost always). Multi-item scales (pain, swallowing, senses, speech, social eating, social contact, and sexuality), and six symptom items (dental problems, opening mouth, dry mouth, sticky saliva, coughing, and feeling ill). Higher scores in the symptom scales demonstrated higher levels of symptoms.
Health-related quality of life (EQ5D)	From the start of immunotherapy until 24 months of follow-up.	EuroQol Five Dimensions Health Questionnaire. Domains: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. It also includes a VAS regarding patients' "Health Today" scored between 0 and 100. Each domain will be converted into categorical values (problems vs no problems).
Disease-specific survival	From the start of immunotherapy until 2 years follow-up.	The length of time a patient survives without death due to disease.
Health-related quality of life (CWS)	From the start of immunotherapy until 24 months of follow-up.	Cancer worry scale. Rated on a Likert-type scale from one (never) to four (almost always), which were summed to produce a total CWS score ranging from 8 to 32, with higher scores indicating more frequent worries about cancer.
Overall survival	From the start of immunotherapy until 2 years follow-up.	The length of time a patient survives after treatment.

Trial Locations

Locations (5)

Maastricht UMC; 🇳🇱 Maastricht, Limburg, Netherlands

Netherlands Cancer Institute - Antoni van Leeuwenhoek; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Amsterdam UMC; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

UMC Utrecht; 🇳🇱 Utrecht, Netherlands