This phase I trial is evaluating how safe and tolerable a new oral drug (IN10018) is, when it is given on it's own and in combination with an oral targeted therapy, for patients with uveal or NRAS-mutant melanoma that has spread to other parts of the bodyA Phase Ib, Open-label Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antitumor Activities of IN10018 as Monotherapy and Combination Therapy in Subjects With Metastatic Melanoma

Exclusion

1. Has had major surgery or significant traumatic injury within 28 days prior to first dose of study treatment, or anticipation of the need for major surgery during study treatment.
2. Has received prior systemic, intrahepatic, or sphere anticancer therapy including investigational agents within 14 days or less than 5 half-lives (whichever is shorter) of chemotherapy or targeted therapy, or within 28 days of immunotherapy, prior to first dose of study treatment.
3. Has received prior radiotherapy or radioactive chemotherapy within 14 days prior to first dose of study treatment.
4. Has received prior treatment of any FAK inhibitor (Parts 1, 2 and 3), or prior treatment of any MEK inhibitor (Parts 2 and 3 only).
5. Has a known previous or concurrent cancer that is distinct in primary site or histology from current melanoma within 3 years prior to first dose of study treatment, except for curatively treated cancers such as cervical carcinoma in situ and indolent cancers with very low likelihood of relapse or progress per investigator judgement.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
7. Diabetes mellitus, insulin dependent and non-insulin dependent with HBA1C > 6.5%, microalbuminuria > 150 mg (24-h collection), and CrCL of < 45ml/min with an adequate 24-hour urine collection.
8. Prior history of Alport syndrome.
9. Recent medical history (with the last 1-year) of acute renal injury, Goodpasture's Syndrome, IgA nephropathy, focal segmental glomerulosclerosis, nephrotic syndrome, parenteral drug abuse, recurrent pyelonephritis, systemic lupus erythematosus, uncontrolled hypertension, vasculitis, and chronic illnesses with potential underlying glomerular renal disease.
10. Has contraindications to anti-PD-1 or anti-PD-L1 immunotherapy (Part 3).
11. Has received prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA4 immunotherapy and was discontinued for significant immunotherapy-related adverse events (Part 3).
12. Current treatment with anti-viral therapy for HBV (Part 3).
13. Prior allogeneic stem cell or solid organ transplantation.
14. Active tuberculosis
15. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina (Part 3).
16. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. (Part 3).
17. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on previous chest computed tomography (CT) scan.

18. Has a history of major cardiovascular, cerebrovascular, or thromboembolic diseases (e.g., congestive heart failure, acute myocardial infarction, unstable angina, atrial fibrillation, ventricular tachyarrhythmia, uncontrolled hypertension, stroke, transient ischemic attack, deep vein thrombosis or pulmonary embolism) within 6 months before first dose of study treatment, or has any of the following abnormality:

    • QTc interval > 480 msec (Fridericia formula), (patients with right bundle branch block is not required to have QTc if the block is stable and assessed as not clinically significant by the PI),
    • Left ventricular ejection fraction (LVEF) < 50%,
    • Arrhythmia with clinical significance, or
    • Other heart diseases with clinical significance.
19. 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), neovascular macular degeneration, or uncontrolled glaucoma with intra-ocular pressures >21 mmHg in the eye(s) unaffected by melanoma. (Parts 2 and 3)
20. Has known uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage prior to the first dose of study treatment.
21. Has malabsorption syndrome or inability to take oral drugs.
22. Has clinically significant gastrointestinal abnormalities including uncontrolled gastrointestinal inflammatory lesions (Crohn's disease, or ulcerative colitis in active or uncontrolled gastrointestinal bleeding).
23. Known allergy or hypersensitivity to IN10018 cobimetinib and/or atezolizumab, or their ingredients.
24. Has had an active infection requiring systemic therapy within 14 days prior to the first dose of study treatment.
25. Has known human immunodeficiency virus (HIV) infection.
26. Has known active Hepatitis B or Hepatitis C virus infection.
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
28. Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.

29. Has had used below CYP3A inhibitors/inducers and P-gp inhibitors within 14 days prior to first dose of study treatment, or anticipation of the need to use them during study treatment:

    • Part 1: Strong CYP3A inhibitors/inducers and P-gp inhibitors are prohibited at least 14 days prior to initiation of and during study treatment.
    • Parts 2 and 3: Moderate and Strong CYP3A inhibitors/inducers and P-gp inhibitors are prohibited at least 14 days prior to initiation of and during study treatment.