This is a phase Ib, open label clinical study to evaluate the safety, tolerability, PK and antitumor activities of IN10018 as monotherapy and in combination with cobimetinib in subjects with metastatic uveal melanoma and NRAS-mutant metastatic melanoma.

Subjects with metastatic uveal melanoma (UM) or with NRAS-mutant metastatic melanoma will be enrolled.

IN10018 will be assessed firstly as monotherapy（Part 1）, then in combination with cobimetinib (Part 2) and in combination with cobimetinib and Atezolizumab (Part 3).

Key Inclusion Criteria:

1. Ability to understand and willingness to sign informed consent(s).

2. Male or female subjects ≥ 18 years at the time of signing informed consent.

3. Histologically or cytologically confirmed metastatic melanoma with subtypes limited to:

   1. Metastatic uveal melanoma, or
   2. Metastatic NRAS-mutant melanoma harboring an NRAS activating mutations of Q61, G12, or G13 mutation per local laboratory (including local reference laboratory) results.

4. Requirements for previous therapy:

   1. Uveal melanoma: Either be treatment naïve or have failed the most recent therapy for metastatic disease, or
   2. NRAS-mutant melanoma: Either be ineligible for standard of care due to the presence of various comorbidities or have failed the most recent therapy such as immunotherapy for metastatic disease.
   3. Have failed immunotherapy therapy (anti-PD-1 or anti-PD-L1) alone or in combination with other agents for metastatic disease either with no initial response or disease progression after an initial response. (Part 3)
   4. Received a minimum of two cycles of anti-PD-1/PD-L1 therapy. (Part 3)

5. Consent to undergo tumor biopsies of accessible lesions, before and during treatment and at radiographic progression, for biomarker analyses (site dependent).

6. At least one measurable lesion can be accurately measured per RECIST 1.1 by investigator.

7. ECOG performance status of 0 or 1.

8. Life expectancy of at least 3 months as assessed by investigator.

9. Availability of fresh tumor tissue and/or archival tumor tissue at Screening if agreed by subjects.

10. Must have recovered from all AEs due to previous therapies to ≤ Grade 1 (CTCAE 5.0) or stable status as assessed by investigator.

11. Adequate bone marrow, liver, renal, and coagulation function within 5 days prior to first dose of study treatment.

12. A male subject must agree to use contraception as detailed in Appendix 4 of this protocol during the treatment period and through 30 days after the last dose of study treatment and must refrain from donating sperm during this period.

13. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:

    1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 4. OR
    2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and through 30 days after the last dose of study treatment.

Key Exclusion Criteria:

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.