high-risk, surgically resectable BRAF mutated and wild-type melanoma MedDRA version: 21.1 Level: LLT Classification code 10053571 Term: Melanoma System Organ Class: 100000004864
Conditions
Sponsors
FONDAZIONE MELANOMA ONLUS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Patients of either sex aged =18 years 2) Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form 3) Patients must have histologically or cytologically confirmed Stage IIIB/C/D or oligometastatic stage IV1 resectable melanoma. The definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumour Conference attended by melanoma medical and surgical oncology staff. Resectable tumours are defined as having no significant vascular, neural or bony involvement. Only cases where a complete surgical resection with tumour-free margins can safely be achieved are defined as resectable 4) Patients must have ARAF and BRAF mutation-positive and CRAF mutation-negative 5) Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team 6) Patients must have measurable disease, defined by RECIST 1.1 7) Eastern Cooperative Oncology Group (ECOG) performance status 0-1 8) Patients must have organ and marrow function as defined below: ¿ ANC =1.5 X 10-9/L ¿ Haemoglobin =9.5 g/dL ¿ Platelets =100 X 10-9/L ¿ PT/INR and PTT =1.5 X upper limit of normal (ULN) ¿ Total bilirubin =1.5 X ULN (isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin =65 years) yes F.1.3.1 Number of subjects for this age range 28
Exclusion criteria
Exclusion criteria: 1) No previous cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug 2) Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any cancer from which the patient has been disease-free for 2 years 3) Any major surgery within the last 3 weeks 4) Pregnancy and/or breast feeding or of childbearing potential and not practicing a reliable method of birth control 5) Unwillingness or inability to follow the procedures required in the protocol. 6) Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity 7) Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels 8) History of uncontrolled cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy 9) Subjects with conditions requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment 10) Prior BRAF or MEK directed therapy; patients who have received prior interferon are eligible 11) History of retinopathy or any finding at ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular de generation 12) Presence of any of the following risk factors for RVO: a) Uncontrolled glaucoma with intra-ocular pressures = 21mmHg; b) Serum cholesterol =Grade 2; c) Hypertriglyceridemia = Grade 2; d) Hyperglycaemia (fasting) =Grade 2 13) Correct QT interval > 450 msec to baseline, history of congenital long QT syndrome 14) Uncontrolled medical condition among which endocrine disorders (such as hypothyroidism, hyperthyroidism and diabetes mellitus) 15) Other severe medical or psychiatric conditions (e.g. depression) or abnormalities of laboratory tests that may increase the risk associated with study participation or the assumption of Vemurafenib and Cobimetinib, or that may interfere with the interpretation of study results, which in the judgment of the Investigator can make the patient not eligible for the study 16) Uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, cerebrovascular accident or transient ischemic attack, pulmonary embolism, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent 17) History of active primary immunodeficiency 18) Receipt of live attenuated vaccine within 30 days prior to the first dose. Note: enrolled patients should not receive live vaccine whilst receiving IMP and up to 30 days after the last dose of IMP 19) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or antiCTLA-4 antibody 20) Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients 21) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) ind
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the pathologic complete response (pCR) rate (Centrally/Independently determined).;Secondary Objective: •Recurrence-free survival (RFS) at 2-years, 3-years and at the end of the study. •Overall survival (OS) defined as the time from randomisation to death. For patients alive at the end of the study time will be censored at the date of last follow-up. •pORR defined as the sum of pathologic complete responses (pCRs), near pathologic complete responses (near pCRs) and pathologic partial responses (pPRs). •Safety: frequency of the following treatment-emergent adverse events (AEs) while on treatment or within 30 days after the last study treatment: All AEs, Grade 3 to 4 5 AEs, serious adverse events (SAEs), deaths, AEs of special interest (AESIs), and AEs leading to treatment discontinuation or withdrawal from the study. •To determine molecular and immunophenotypic changes in tumour and peripheral blood evaluating several biomarkers. Since the identification of new markers for immunotherapy is rapidly evolving, the definitive list of analyses remains to be determined.;Primary end point(s): pathological Complete Response Rate (pCR);Timepoint(s) of evaluation of this end point: 68 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Recurrence-Free Survival (RFS) at 2-years, 3-years and at the end of the study. RFS defined as the time from randomisation to recurrence event (local or distant disease development, or death). For patients without events at the end of the study time will be censored at the date of last followup. 2. Overall Survival (OS) defined as the time from randomisation to death. For patients alive at the end of the study time will be censored at the date of last follow-up. 3. pORR defined as the sum of pathologic complete responses (pCRs), near pathologic complete responses (near pCRs) and pathologic partial responses (pPRs). 4. Safety: • Frequency of the following treatment-emergent adverse events (AEs) while on treatment or within 30 days after the last study treatment: • All AEs, Grade 3 to 4 AEs, serious adverse events (SAEs), deaths, AEs of special interest (AESIs), and AEs leading to treatment discontinuation or withdrawal from the study 5. To determine molecular and immunophenotypic changes in tumour and peripheral blood evaluating several biomarkers. Since the identification of new markers for immunotherapy is rapidly evolving, the definitive list of analyses remains to be determined. The following tests are planned (differences: baseline at surgery, during adjuvant treatment and at recurrence, will be compared). - Immunoscore (densities of tumour-infiltrating CD3 and CD8 cells), as well as PD-L1 expression on tumour and immune cells, evaluated by IHC analysis with an automated quantification system and a standardized assay on tumour tissue; - Circulating cytokines and chemokines profiling, evaluated by luminex technology in patient peripheral blood samples; - Myeloid-derived suppressors cells (MDSCs) and immune cell subtypes expression and lymphocyte activation, evaluated by multicolourcytofluorimetric approach in patient peripheral blood samples; - Metabolomic profiling in patient peripheral blood samples, evaluated by nuclear ma | — |
Countries
Italy
Contacts
Public ContactClinical Operations
Clinical Research Technology Srl
Outcome results
None listed