Retifanlimab for Merkel cell carcinoma

Inclusion criteria

• {"criterion_text":"- Signed informed consent\n- 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\n- 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\n- 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\n- Willingness to comply with scheduled visits, treatment plan, laboratory tests and other study procedures\n- Subjects must be 18 years old or older\n- ECOG performance status of 0 to 1\n- 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\n- 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\n- No prior systemic treatment or neoadjuvant radiation therapy\n- 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\n- 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\n- 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."}

Exclusion criteria

• {"criterion_text":"- Prior systemic therapy for MCC, including chemotherapy and prior PD-1 or PD-L1-directed therapy\n- History of organ transplant, including allogeneic stem cell transplantation\n- 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\n- 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\n- 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\n- Active infections requiring systemic therapy, or systemic antibiotic use up to 10 days before Cycle 1 Day 1\n- Live vaccines within 28 days prior to and for a duration of 90 days after the administration of study drug are forbidden\n- Known hypersensitivity to platinum, etoposide or any of the excipients that cannot be controlled with standard measures (eg, antihistamines, corticosteroids)\n- Known allergy or hypersensitivity to any component of the study drug formulation\n- Subjects who lack the ability or are unlikely, in the opinion of the investigator, to comply with the Protocol requirements\n- Subjects who are pregnant or breastfeeding\n- Primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine\n- Treatment with anticancer drugs, radiation therapy or participation in another interventional clinical study within 28 days before the first administration of study drug\n- Distant metastases at any site\n- 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\n- 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.\n- 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\n- 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)\n- Evidence of interstitial lung disease or active noninfectious pneumonitis"}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"pCR measured as percentage of patients (ITT population) achieving pathological complete response per central pathological review; pCR defined as absence of residual viable invasive cancer in the complete resected tumor specimen and all sampled regional lymph nodes."}

Secondary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Assessment via collection and reporting of adverse events (including SAEs), laboratory data, vital signs, ECGs, and drug exposure for all treated patients."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Quality of life assessed with patient-reported outcome questionnaires (FACT-M, EQ-5D-5L); analyses based on Fatigue Assessment Scale (FAS)."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Spatial profiling of gene expression in matched pre- and post-treatment tumor samples to evaluate transcriptional changes in tumor and microenvironment compartments."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Ultra-deep whole-exome sequencing with UMIs on longitudinal liquid biopsies to track ctDNA mutational profiles and clearance; correlation with pCR will be assessed."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Assessment of MCPyV status and PD-(L)1 expression on matched pre/post tumor tissue sections; evaluation of inhibitory receptors/ligands in malignant and stromal cells and correlation with regimen activity."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Time-to-event endpoint measured from enrollment to recurrence or death; censoring at last follow-up if disease-free."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Time from enrollment to death from any cause; censoring at last known alive date for survivors."}

Italy

Earliest CTIS Part Ii Submission Date

26-11-2024

Latest Decision Or Authorization Date

21-01-2025

Processing Time Days

56

Number Of Sites

13

Number Of Participants

36

Primary sponsor

Full Name

Gruppo Oncologico Del Nord Ovest

Organisation Type

Patient organisation/association

Country Of Registered Address

Italy

Third parties

• {"country":"Italy","full_name":"Fondazione IRCCS Istituto Nazionale Dei Tumori","duties_or_roles":"Biological sample storage and X-ray images","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Italy","full_name":"Gruppo Oncologico Del Nord Ovest","duties_or_roles":"1","organisation_type":"Patient organisation/association"}
• {"country":"Italy","full_name":"Opis S.r.l.","duties_or_roles":"12","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"DataRiver","duties_or_roles":"Electronic Data Collection Sheet","organisation_type":"SME"}
• {"country":"Italy","full_name":"Fondazione IRCCS Istituto Nazionale Dei Tumori","duties_or_roles":"Early review of safety data","organisation_type":"Hospital/Clinic/Other health care facility"}