Combination or Sequence of Vemurafenib, Cobimetinib, and Atezolizumab in High-risk, Resectable Melanoma

Exclusion Criteria

• •1. Currently receiving 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. Patients with a history of uncontrolled cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy;
• •9. Subjects with a condition 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, retinal vein occlusion (RVO), or neovascular macular de generation;
• •12. Presence of any of the following risk factors for RVO: a) Uncontrolled glaucoma with intraocular pressures ≥ 21mmHg; b) Serum cholesterol ≥Grade 2; c) Hypertriglyceridemia ≥ Grade 2; d) Hyperglycaemia (fasting) ≥Grade 2;
• •13. Correct QT interval \> 450msec to baseline, history of congenital long QT syndrome;
• •14. Uncontrolled medical condition among which endocrine disorders (such as hypothyroidism, hyperthyroidism and diabetes mellitus);
• •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 of IMP. Note: Patients, if enrolled, 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 anti-CTLA-4 antibody;
• •20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients;
• •21. Positive test for HBV sAg or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
• •22. Known history of testing positive for HIV or known AIDS;
• •23. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.