Towards Cure Via Only Ultra-short ICB in CSCC (MATISSE 2)

Towards Organ Preservation and Cure Via Immunotherapy in Cutaneous Squamous Cell Carcinoma Patients, Normally Undergoing Morbid Curative Surgery and Radiotherapy. The MATISSE 2 Trial, an Investigator-initiated Multicentre Phase 2 Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Cutaneous Squamous Cell Carcinoma of the Head and Neck; Cutaneous Squamous Cell Carcinoma; Cutaneous Squamous Cell Cancer; Cutaneous Squamous Cell Carcinoma (CSCC)
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilumimab

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 Type: Interventional
• Enrollment (Estimated): 41
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lotje Zuur, Prof. Dr.; Phone Number: +31205129111; Email: c.zuur@nki.nl
• Study Contact Backup: Name: Stan W. van Dijk, MD; Phone Number: +31205129111; Email: matisse2@nki.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CX
    • Not yet recruiting
    • UMC Utrecht
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229HX
      • Not yet recruiting
      • Maastricht UMC
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105AZ
      • Not yet recruiting
      • Amsterdam UMC
    • Amsterdam, Noord-Holland, Netherlands, 1066CX
      • Recruiting
      • Netherlands Cancer Institute - Antoni van Leeuwenhoek
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015GD
      • Not yet recruiting
      • Erasmus MC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant nivolumab + ipilimumab; Intravenous neoadjuvant nivolumab 3 mg/kg in week 0 and 2 in combination with intravenous neoadjuvant ipilimumab 1 m/kg in week 0.	Drug: Nivolumab; 3 mg/kg; Other Names: Immunotherapy; Drug: Ipilumimab; 1 mg/kg; Other Names: Immunotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of clinical complete remission after only immunotherapy	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.	From the start of immunotherapy until 24 months of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of clinical complete remission after only immunotherapy	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	From the start of immunotherapy until 12 and 18 months of follow-up.
Immune-related adverse events	The rate and type of immune-related adverse events (CTCAE v5.0, Clavien-Dindo).	From the start of immunotherapy until 100 days after the last course of immunotherapy.
Health-related quality of life (EORTC QLQ-C30)	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.	From the start of immunotherapy until 24 months of follow-up.
Health-related quality of life (EORTC QLQ-H&N35)	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.	From the start of immunotherapy until 24 months of follow-up.
Health-related quality of life (EQ5D)	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).	From the start of immunotherapy until 24 months of follow-up.
Health-related quality of life (CWS)	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.	From the start of immunotherapy until 24 months of follow-up.
Health-related quality of life (IT)	Immunotherapy questionnaire. Rated on a Likert-type scale from one (never) to four (almost always), to evaluate toxicity after immunotherapy treatment.	From the start of immunotherapy until 24 months of follow-up.
Health-related quality of life (sexuality questionnaire)	Rated on a Likert-type scale from one (never) to four (almost always), to evaluate problems in sexual functioning.	From the start of immunotherapy until 24 months of follow-up.
Treatment duration	Total duration of received treatment	From the start of immunotherapy until the end of treatment (average 6 weeks)
Treatment stops	The amount of times and the length of time the immunotherapy, surgery or adjuvant radiotherapy had to be stopped.	From the start of immunotherapy until the end of treatment (average 6 weeks)
Disease-specific survival	The length of time a patient survives without death due to disease.	From the start of immunotherapy until 2 years follow-up.
Recurrence-free survival	The length of time a patient survives without recurrent disease.	From the start of immunotherapy until 2 years follow-up.
Event-free survival	The length of time a patient survives without recurrent disease or death of any cause.	From the start of immunotherapy until 2 years follow-up.
Overall survival	The length of time a patient survives after treatment.	From the start of immunotherapy until 2 years follow-up.
Healthcare consumption	Healthcare consumption during the trial.	From the start of immunotherapy until 24 months of follow-up.
Cost-effectiveness	The incremental cost-effectiveness ratio between quality-adjusted life years and the cost of trial-related healthcare.	From the start of immunotherapy until 24 months of follow-up.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor micro-environment (IHC)	Temporal and spatial analyses of the TME in the lymph nodes and primary tumours will be explored using immunohistochemistry (e.g. PD-L1 expression, CPS score).	From enrollment until week 5
Tumor micro-environment (RNAseq)	Temporal and spatial analyses of the TME in the lymph nodes and primary tumours will be explored using bulk and single-cell RNA-sequencing.	From enrollment until week 5
Tumor micro-environment (spatial mass cytometry)	Temporal and spatial analyses of the TME in the lymph nodes and primary tumours will be explored using spatial mass cytometry.	From enrollment until week 5
Immune dynamics (PBMC)	Temporal immune dynamics in peripheral blood will be investigated via peripheral blood mononuclear cells (PBMCs).	From enrollment until week 5
Immune dynamics (TCR)	Temporal immune dynamics in peripheral blood will be investigated via TCR analyses of peripheral immune cells in comparison to intratumoural immune cells	From enrollment until week 5
ctDNA	The ctDNA in peripheral blood using CyclomicsSeq	From enrollment until week 5.
Complement activation	Complement activation, complement mediated neutrophil activation in the TME and their contribution on the immune response during neoadjuvant immunotherapy	From enrollment until week 5
Humoural immunity	Activation of humoral immunity, and specifically treatment-induced changes in antibody production and their relation with treatment response	From enrollment until week 5

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Maastricht University Medical Center; UMC Utrecht; Erasmus Medical Center; Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Lotje Zuur, Prof. Dr., The Netherlands Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2025
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: January 7, 2025
• First Submitted That Met QC Criteria: February 6, 2025
• First Posted (Actual): February 12, 2025

Study Record Updates

• Last Update Posted (Actual): May 29, 2025
• Last Update Submitted That Met QC Criteria: May 22, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: neoadjuvant; immunotherapy; nivolumab; checkpoint inhibitors; intravenous; ipilimumab; opdivo; yervoy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Squamous Cell Carcinoma of Head and Neck; Carcinoma; Carcinoma, Squamous Cell; Neoplasms, Squamous Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nivolumab; Immunomodulating Agents; Immunologic Factors
• Other Study ID Numbers: M24MAT; 2024-516152-17-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No