Patients with hardly resectable/unresectable limited metastasis in malignant melanoma stages IIIC/IV (American Joint Committee on Cancer (AJCC) 2010) carrying the BRAF V600 mutation, in order to achieve operability. MedDRA version: 20.0 Level: PT Classification code 10025671 Term: Malignant melanoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10025670 Term: Malignant melanoma stag
Conditions
Interventions
Trade Name: ZELBORAF
Product Name: Vemurafenib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VEMURAFENIB
CAS Number: 918504-65-1
Concentration unit: mg milligram(s)
Concentration type:
Sponsors
University Hospital Tübingen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must meet the following criteria for study entry: 1. Signed Informed Consent Form 2. Age = 18 years 3. Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) mela-noma, as defined by AJCC, 7th revised edition a. Naïve to prior systemic anti-cancer therapy for melanoma, with the following exceptions: Adjuvant treatment with interferon (IFN), In-terleukin-2 (IL-2), or vaccine therapies, if dis-continued at least 28 days prior to initiation of study treatment b. Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to initiation of study treatment 4. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue through use of a clinical mutation test approved by the local health authority. If archival tumor tissue is unavailable or is de-termined to be inadequate, tumor tissue must be obtained from a biopsy performed at screening. 5. Eastern Cooperative Oncology Group Performance Status (ECOG) of 0 or 1 6. Decision of eligibility for neoadjuvant combined vem+cobi+atezo treatment by interdisciplinary tumor board. Patient with limited numbers of metastases and few organ systems involved should be selected, making surgical resection after neo-adjuvant treatment probable. 7. Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST V1.1) criteria (must be outside the central nervous system (CNS)) 8. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, with the exception of amylase, lipase, and lactate dehydrogenase (LDH) where up to 28 days is acceptable (using central laboratory result) • Absolute neutrophil cells (ANC) = 1.5 × 109/L without granulocyte colony-stimulating factor support • White blood cells (WBC) count = 2.5 × 109/L • Lymphocyte count = 0.5 × 109/L • Platelet count = 100 × 109/L without transfu-sion • Hemoglobin = 9 g/dL without transfusion • Serum albumin = 2.5 g/dL • Total bilirubin = 1.5 × the upper limit of normal (ULN) • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.0 x ULN • Amylase and lipase = 1.5 x ULN • Alkaline phosphatase (ALP) = 2.5 × ULN or, for patients with documented liver or bone metastases, ALP = 5 × ULN • Serum creatinine = 1.5 × ULN or creatinine clearance (CrCl) = 40mL/min on the basis of measured CrCl from a 24-hour urine collection or Crockcroft-Gault glomerular filtration rate estimation: ? CrCL= ((140-age) x (weight in kg) x (72 x (serum creatinine in mg/dL)-1) (x 0.85 if female) • For patients not receiving therapeutic antico-agulation: international normalized ratio (INR) or activated partial thromboplastin time aPTT = 1.5 × ULN within 28 days prior to initiation of study treatment • For patients receiving therapeutic anticoagu-lation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment 9. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: a. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same perio
Exclusion criteria
Exclusion criteria: 1. Candidates for direct surgery: patients with single site easily resectable metastasis 2. Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment 3. Palliative radiotherapy within 14 days prior to initiation of study treatment 4. Active malignancy (other than BRAFV600 mutation-positive melanoma) or malignancy within 3 years prior to screening 5. A history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration 6. History of clinically significant cardiac dysfunction, 7. Untreated or actively progressing CNS lesions (carcinomatous meningitis) 9. History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm) 10. History of leptomeningeal metastatic disease 11. Anticipated use of any concomitant medication during or within 7 days prior to initiation of study treatment that is known to cause QT prolongation. Patients with regular amiodaron intake in the last 365 days cannot be included 12. Uncontrolled diabetes or symptomatic hyperglycemia 13. History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment 14. Pregnancy or lactation period or intention to become pregnant during the study. 15. Prior allogeneic stem cell or solid organ transplantation 16. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan 17. Active or history of autoimmune disease or immune deficiency (for details see 10.1.2.5 and Appendix 8). 18. Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease 19. Active tuberculosis 20. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia 21. Any Grade = 3 hemorrhage or bleeding event within 4 weeks prior to initiation of study treatment 22. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to initiation of study treatment 23. Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) or any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or could jeopardize the safety of the patient and their compliance in the study 24. Signs or symptoms of clinically relevant infection and/or treatment with therapeutic systemic antibiotics within 2 weeks prior to initiation of study treatment 25. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study 26. Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Percent of patients who become resectable and are resected (surgery decided in multidisciplinary tumor board and no residual lesion detectable after surgery);Secondary Objective: - Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment. - Overall survival time after resection, in the group who actually underwent complete resection - Rate of objective responses - Tolerability - OS and PFS time in the total study population ;Primary end point(s): The primary endpoint is the percentage of patients becoming operable after the combined treatment within 12 weeks. ;Timepoint(s) of evaluation of this end point: after the combined treatment within 12 (+6) weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment. - Overall survival time after resection, in the group who actually underwent complete resection - Rate of objective responses - Tolerability - Overall survival (OS) and progression free survival time in the total study population ;Timepoint(s) of evaluation of this end point: - Progression free survival time after resection - In the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment. - Overall survival time after resection - In the group who actually underwent complete resection: day of death or end of study - Rate of objective responses: every 6 weeks - Tolerability: during the whole study - Overall survival and progression free survival time in the total study population: study enrolement until the day of progression/death | — |
Countries
Austria, Germany
Contacts
Public ContactDepartment of Dermatology
University Hospital Tübingen
Outcome results
None listed