Study aimed at testing the activity of a course of chemo-immunotherapy with retifanlimab combined with platinum-etoposide followed by surgery in patients with operable Merkel cell carcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Jan 2025 → ongoing

Decision date (initial)

2025-01-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-516316-13-00

EudraCT number

2022-000601-27

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of this trial is to assess the activity of the 1 cycle of preoperative retifanlimab plus platinum-etoposide chemo-immunotherapy regimen as measured in terms of pathological complete response (pCR).

Secondary objectives 9

1. To assess the safety and the tolerability of the short-course preoperative chemo-immunotherapy study regimen and to describe the morbidity of surgical procedures.
2. To assess the impact of the short-course preoperative chemo-immunotherapy study regimen on patients’ quality of life.
3. To perform tumor tissue spatial profiling of matched pre- and post-treatment samples to uncover transcriptional tumor/microenvironmental/immune changes induced by the short-course preoperative chemo-immunotherapy study regimen.
4. To evaluate the changes in systemic immune response profiles induced by the short-course preoperative chemo-immunotherapy study regimen.
5. To perform ultra-deep sequencing of circulating tumor DNA (ctDNA) in liquid biopsies to track ctDNA clearance, lack of detectable minimal residual disease and treatment resistance mechanisms by mathematical/computational modeling.
6. To assess the association of tumor Merkel cell polyomavirus (MCPyV) status and the expression of immune checkpoints (including PD-L1) with the activity of the short-course preoperative chemo-immunotherapy study regimen.
7. To identify correlations between Tumor Mutational Burden (TMB) and the activity of the short-course preoperative chemo-immunotherapy study regimen.
8. To assess the relapse-free survival (RFS) achieved by the short-course preoperative chemo-immunotherapy study regimen followed by standard treatment management.
9. To assess the overall survival (OS) achieved by the short-course preoperative chemo-immunotherapy regimen followed by standard treatment management.

Conditions and MedDRA coding

Merkel cell carcinoma without metastases in other organs and surgically resectable

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed informed consent
2. Subjects must be 18 years old or older
3. ECOG performance status of 0 to 1
4. Histologically confirmed diagnosis of MCC amenable for radical surgery as defined by local or institutional surgical practices, based on multidisciplinary team assessment. Subjects must have one of the following stages of disease: a. Stage IIA - IIB- III (according to the AJCC staging system 8th edition) b. Local/Regional recurrent disease after primary surgery, as defined as total disease burden ≥ 1 cm diameter amenable for a radical intent surgery
5. Able to provide archival FFPE tumor samples (if collected within three months from study enrollment) or have a tumor amenable to pre-treatment biopsy. Excisional, incisional, or core-needle samples are acceptable. Fine needle aspirates are not allowed
6. No prior systemic treatment or neoadjuvant radiation therapy
7. Adequate bone marrow function characterized by the following at screening: a. Platelets ≥ 100 × 109/L b. Absolute neutrophil count (ANC) ≥1.5 x 109/L c. Hemoglobin ≥ 9.0 g/dL
8. Adequate renal function characterized by serum creatinine ≤ 1.5 × upper limit of normal (ULN) OR calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 60 mL/min at screening for subject receiving cisplatin OR creatinine clearance ≥ 50 mL/min at screening for subject receiving carboplatin
9. Adequate hepatic function characterized by the following at screening: a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL. Note: Subjects with Serum total bilirubin ≥ 1.5 × ULN and conjugated bilirubin ≤ ULN or < 40% of total bilirubin are allowed. b. AST (SGOT) and/or ALT (SGPT) <2.5 x UNL.
10. Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 6 months after the administration of study treatment and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed
11. Women of childbearing potential must have a negative serum pregnancy test at screening and before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through 180 days after the administration of any study drug. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed
12. Women of non-childbearing potential (i.e. surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible
13. Willingness to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion criteria 19

1. Prior systemic therapy for MCC, including chemotherapy and prior PD-1 or PD-L1-directed therapy
2. Primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine
3. Treatment with anticancer drugs, radiation therapy or participation in another interventional clinical study within 28 days before the first administration of study drug
4. Distant metastases at any site
5. Any known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry except for cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy
6. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft [CABG], coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment; b. Symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except atrial fibrillation and paroxysmal supraventricular tachycardia.
7. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
8. History of chronic conditions (i.e. COPD) requiring systemic immune-suppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg of prednisone or equivalent)
9. Evidence of interstitial lung disease or active noninfectious pneumonitis
10. History of organ transplant, including allogeneic stem cell transplantation
11. History or current evidence of any condition, therapy or laboratory abnormality that might interfere with the subject’s participation to the study or is not in the best interest of the subject to participate, in the opinion of the treating investigator
12. Know active hepatitis B [positive HBV surface antigen (HBsAg) result] or hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
13. Known uncontrolled HIV infection. HIV-positive patients are eligible if their CD4+ cell count amounts to 300 cells per μL or more; HIV viral load must be undetectable per standard of care assay, and they have to be compliant with antiretroviral treatment
14. Active infections requiring systemic therapy, or systemic antibiotic use up to 10 days before Cycle 1 Day 1
15. Live vaccines within 28 days prior to and for a duration of 90 days after the administration of study drug are forbidden
16. Known hypersensitivity to platinum, etoposide or any of the excipients that cannot be controlled with standard measures (eg, antihistamines, corticosteroids)
17. Known allergy or hypersensitivity to any component of the study drug formulation
18. Subjects who lack the ability or are unlikely, in the opinion of the investigator, to comply with the Protocol requirements
19. Subjects who are pregnant or breastfeeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The study primary endpoint will be the pathological complete response rate or pCR rate, defined as the percentage of patients, relative to the total of enrolled subjects in the intention-to-treat population, who will achieve a pathological complete response, as per central pathological review. Pathological complete response will be defined as the absence of residual viable invasive cancer on evaluation of the complete resected tumor specimen and all sampled regional lymph nodes.

Secondary endpoints 7

1. Safety and tolerability will be assessed in terms of AEs (including SAEs), laboratory data, vital signs, ECGs, and exposure, that will be collected for all patients enrolled in the trial and receiving retifanlimab plus platinum-etoposide chemo-immunotherapy regimen.
2. Quality of life will be defined by a series of Patient Reported Outcomes (PROs) assessed by the completion of quality-of-life questionnaires, FACT-M Questionnaire and EQ-5D-5L, during the preoperative treatment phase. All PROs analyses will be based on the Fatigue Assessment Scale (FAS)
3. The transcriptional tumor/microenvironmental changes induced by the short-course preoperative chemo-immunotherapy study regimen will be resolved spatially by the evaluation of the gene expression profiles in different tumor compartments in matching pre- and post-treatment samples.
4. The correlation of pCR with ctDNA mutational profiles and its clearance after the short-course preoperative treatment will be assessed by using ultra-deep whole-exome sequencing with Unique Molecular Identifiers to evaluate with high accuracy the presence of ctDNA obtained from the longitudinally collected liquid biopsies with high accuracy
5. The correlation of tumor Merkel cell polyomavirus (MCPyV) status and PD-L1 expression of with the activity of the short-course preoperative chemo-immunotherapy study regimen will be done assessing MCPyV on matching tumor tissue sections collected pre- and post-treatment. The evaluation inhibitory receptors and ligands (PD-1, PD-L) will be carried out in the malignant cells and in the stroma cells
6. Relapse Free Survival will be defined as the time from enrollment to the first documentation of disease recurrence or death due to any cause, whichever occurs first. RFS will be censored on the date of the last follow-up visit documenting absence of disease for patients who are alive, on study and disease free at the time of the analysis
7. Overall survival will be defined as the time from enrollment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 5

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications