Neo-adjuvant Nivolumab or Nivolumab With Ipilimumab in Advanced Cutaneous Squamous Cell Carcinoma Prior to Surgery (MATISSE)

• ClinicalTrials.gov Identifier: NCT04620200
• Recruitment Status: Recruiting
• First Posted: November 6, 2020
• Last Update Posted: October 26, 2022
• Sponsor: The Netherlands Cancer Institute
• Information provided by (Responsible Party): The Netherlands Cancer Institute

Study Description

Brief Summary:

To determine the histopathological response rate to neo-adjuvant nivolumab and nivolumab plus ipilimumab at time of standard of care(surgery ± radiotherapy).in patients with cutaneous squamous cell carcinoma.

Condition or disease	Intervention/treatment	Phase
Cutaneous Squamous Cell Carcinoma	Drug: Nivolumab; Drug: Ipilimumab	Phase 2

Detailed Description:

This is an investigator-initiated randomized non-comparative phase II trial consisting of 40 patients with resectable stage III-IVa CSCC randomized 1:1 to ARM A: 2 courses of nivolumab 3 mg/kg in week 0 and 2, or ARM B: 2 courses of nivolumab 3 mg/kg in week 0 and 2 plus 1 course of ipilimumab 1mg/kg in week 0. Both treatment arms are neo-adjuvant and applied prior to standard of care (consisting of surgery at week 4 with or without adjuvant radiotherapy).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Neo-adjuvant Nivolumab or Nivolumab With Ipilimumab in Advanced Cutaneous Squamous Cell Carcinoma Patients Prior to Standard of Care Surgery; the MATISSE Trial
• Actual Study Start Date: August 11, 2020
• Estimated Primary Completion Date: November 1, 2022
• Estimated Study Completion Date: November 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: ARM A; 2 courses of nivolumab 3 mg/kg in week 0 and 2 prior to standard of care	Drug: Nivolumab; 3mg/kg; Other Name: immunotherapy
Experimental: ARM B; 2 courses of nivolumab 3 mg/kg in week 0 and 2 plus 1 course of ipilimumab 1mg/kg in week 0 prior to standard of care	Drug: Nivolumab; 3mg/kg; Other Name: immunotherapy; Drug: Ipilimumab; 1mg/kg; Other Name: immunotherapy

Outcome Measures

Primary Outcome Measures :

1. Histopathological response rate at standard of care [ Time Frame: At time of standard of care at week 4 ]
   The proportion of viable tumor cells left in the resected specimen, to neo-adjuvant nivolumab and nivolumab plus ipilimumab at time of SOC (surgery ± RT).

Secondary Outcome Measures :

1. Sensitivity and specificity of tumor biopsies, clinical photography, FDG-PET and (functional)MRI compared to the histopathological tumor response to neo-adjuvant immunotherapy [ Time Frame: At time of standard of care at week 4 ]
   Histopathological tumor response to neo-adjuvant immunotherapy as measured in the tumor resection specimen will be compared to the tumor response as measured via serial tumor biopsies, the tumor biopsy at time of surgery and imaging (clinical photography, FDG-PET and (f)MRI). Histopathologic response in the tumor biopsies will be defined similarly as histopathologic response in the resected specimen. Response at imaging studies will be measured as follows: Clinical photography via specific clinical observation criteria, FDG-PET via RECIST 1.1 criteria and % change in TLG or MTV and (f)MRI via RECIST 1.1
2. Numbers of participants without significant delay (>1 week) or cancelation of SOC surgery due to immune-related toxicity [ Time Frame: At time of standard of care at week 4 ]
3. Recurrence free survival (RFS) at 2 years FU of responders versus non-responders to neo-adjuvant ICI [ Time Frame: At 2-years follow up ]
4. Overall survival (OS) at 2 years FU of responders versus non-responders to neo-adjuvant ICI [ Time Frame: At 2-years follow up ]
5. The number of patients with AE (rate and type) acoording to NCI CTCAE v.5.0 up to 2 years FU after SOC [ Time Frame: At 2-years follow up ]
6. Clinical response of potentially additional AK surface areas after ICI identified by digital clinical photography on day 0, day 14, day 28 and every 6 months during FU up to 2 years. [ Time Frame: On day 0, day 14, day 28 (at time of surgery) and every 6 months during FU up to 2 years. ]
7. Quality of life as measured by EORTC QLQ-C30 [ Time Frame: At baseline, at surgery (week 4) and after 3, 6, 9, 12, 18 and 24 months during FU ]
   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.
8. Quality of life as measured by H&N 35 [ Time Frame: At baseline, at surgery (week 4) and after 3, 6, 9, 12, 18 and 24 months during FU ]
   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 (teeth problems, opening mouth, dry mouth, sticky saliva, coughing, and feeling ill). Higher scores in the symptom scales demonstrated higher levels of symptoms.
9. Quality of life as measured by the EQ5D, [ Time Frame: At baseline, at surgery (week 4) and after 3, 6, 9, 12, 18 and 24 months during FU ]
   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).
10. Quality of life as measured by the cancer worry scale (CWS) [ Time Frame: At baseline, at surgery (week 4) and after 3, 6, 9, 12, 18 and 24 months during FU ]
    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.
11. Quality of life as measured by the IT questionnaire [ Time Frame: At baseline, at surgery (week 4) and after 3, 6, 9, 12, 18 and 24 months during FU ]
    Rated on a Likert-type scale from one (never) to four (almost always), to evaluate toxicity after immunotherapy treatment.
12. Quality of life as measured by the sexuality questionnaire [ Time Frame: At baseline, at surgery (week 4) and after 3, 6, 9, 12, 18 and 24 months during FU ]
    Rated on a Likert-type scale from one (never) to four (almost always), to evaluate problems in sexual functioning.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

   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.

Exclusion Criteria:

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

Contacts and Locations

Contacts

Contact: Thomas Boere, MD; + 31 0205129111; th.boere@nki.nl

Locations

Netherlands

NKI-AVL; Recruiting

Amsterdam, Noord Holland, Netherlands, 1066CX

Contact: Thomas Boere, MD + 31 0205129111

Sponsors and Collaborators

The Netherlands Cancer Institute

Investigators

• Principal Investigator: Lotje Zuur, MD, PHD; Nehterlands cancer institute

More Information

• Responsible Party: The Netherlands Cancer Institute
• ClinicalTrials.gov Identifier: NCT04620200
• Other Study ID Numbers: N20MAT
• First Posted: November 6, 2020
• Last Update Posted: October 26, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data will not be transferred.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by The Netherlands Cancer Institute:

immunotherapy; neoadjuvant; nivolumab; ipilimumab

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Squamous Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Nivolumab; Ipilimumab; Immunologic Factors; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs