Neoadjuvant Vemurafenib + Cobimetinib + Atezolizumab in Melanoma: NEO-VC

Exclusion Criteria

• •1. Candidates for direct surgery: patients with single site easily resectable metasta-sis
• •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 malig-nancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected BCC, resected cuSCC, resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the patient has been disease-free for at least 3 years
• •a. Patients with a history of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.
• •5. A history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, CSCR, RVO, or ne-ovascular macular degeneration
• •a. Patients will be excluded from study participation if they currently are known to have any of the following risk factors for RVO: i. History of serous retinopathy ii. History of RVO iii. Evidence of ongoing serous retinopathy or RVO at baseline
• •6. History of clinically significant cardiac dysfunction, including the following:
• •1. Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99mmHg despite opti-mal medical management
• •2. Unstable angina, or new-onset angina within 3 months prior to initiation of study treatment
• •3. Symptomatic congestive heart failure, defined as NYHA Class II or higher
• •4. Myocardial infarction within 3 months prior to initiation of study treatment
• •5. Unstable arrhythmia
• •6. History of congenital long QT syndrome
• •7. QTcF ≥480 ms at screening, or uncorrectable abnormalities in serum electro-lytes
• •8. LVEF below the institutional lower limit of normal or below 50%, whichever is lower
• •7. Untreated or actively progressing CNS lesions (carcinomatous meningitis)
• •8. Patients with a history of CNS lesions are eligible, provided that all of the following criteria are met:
• •1. Measurable disease, per RECIST v1.1, must be present outside the CNS
• •2. All known CNS lesions have been treated with radiotherapy or surgery
• •3. CNS lesions have not been treated with whole-brain radiotherapy, except in patients who underwent definitive resection of or stereotactic therapy for all radiologically detectable parenchymal brain lesions
• •4. Absence of interim progression must be confirmed by radiographic study within 4 weeks prior to initiation of study treatment. If new CNS metastases are suspected during the screening period, a confirmatory radiographic study is required prior to initiation of study treatment
• •5. Any radiotherapy or surgery must be completed ≥ 4 weeks prior to initiation of study treatment
• •6. There is no ongoing requirement for corticosteroids, and any prior corticosteroid treatment must be discontinued ≥ 2 weeks prior to initiation of study treatment. Treatment with an anticonvulsant at a stable dose is allowed
• •7. No history of intracranial hemorrhage from CNS lesions
• •9. History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the optic apparatus
• •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.
• •a. WOCBP must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment
• •15. Prior allogeneic stem cell or solid organ transplantation
• •16. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• •a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• •17. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus ery-thematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
• •a. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for the study after discussion with and approval by the Medical Monitor b. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for the study after discussion with and approval by the Medical Monitor c. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with der-matologic manifestations only are eligible for the study provided all of following conditions are met: i. Rash must cover \< 10% of body surface area ii. Disease is well controlled at baseline and requires only low-potency topical corticosteroids iii. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral cor-ticosteroids within the previous 12 months
• •18. Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease including:
• •1. Positive HIV test at screening
• •2. Active HBV infection, defined as having a positive HBsAg test at screening Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total HBcAb test at screening, are eligible for the study
• •3. Active HCV infection, defined as having a positive HCV antibody test and a positive HCV RNA test at screening
• •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 at-tack within 6 months prior to initiation of study treatment
• •23. Current severe, uncontrolled systemic 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
• •a. Patients receiving prophylactic antibiotics are eligible for the study
• •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 within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the study
• •1. Patients who have received acute, low-dose systemic immunosuppressant medication ≥ 4 weeks prior to ini-tiation of study treatment or a one-time pulse dose of systemic immunosup-pressant medication are eligible for the study.
• •2. The use of inhaled corticosteroids for chronic obstructive pulmonary disease or asthma, mineralocorticoids , or low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
• •27. Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells
• •28. Known hypersensitivity to any component of the atezo, cobi, or vem formulations
• •29. History of severe allergic, anaphylactic or other hypersensitivity reactions to chi-meric or humanized antibodies or fusion proteins
• •30. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 4 weeks of the start of study treatment.
• •31. Inability or unwillingness to swallow pills
• •32. Any psychological, familial, sociological, or geographical conditions that may hamper compliance with the protocol and follow-up after treatment discontinuation
• •33. Requirement for concomitant therapy or food that is prohibited during the study, as described in Sections 10.10 and 10.11.
• •34. Patient is unable to comply with the study protocol for any other reason