Phase Ib Study of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies

Exclusion Criteria

• •1. Prior treatment with a MAPK pathway inhibitor
• •2. Clinically significant cardiac disease or risk factors
• •3. Use of any agent known to prolong the QT interval unless it can be permanently discontinued for the duration of study (see list in Section 6.2.2).
• •4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO
• •5. Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs
• •6. Symptomatic CNS metastases which are neurologically unstable
• •7. Insufficient bone marrow function at screening:
• •1. Absolute Neutrophil Count (ANC) \< 1.5 x 109/L.
• •2. Hemoglobin \< 9.0 g/dL.
• •3. Platelets \< 75 x 109/L for TNO155 plus spartalizumab combination; \< 100 x 109/L for TNO155 plus ribociclib combination.
• •8. Insufficient hepatic or renal function at screening:
• •1. Serum total bilirubin \> upper limit of normal (ULN) or, for TNO155 plus spartalizumab combination only, if liver metastases are present at baseline, serum total bilirubin \> 1.5 x ULN. An exception for either combination is for patients with Gilbert's syndrome, who are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN
• •2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 x ULN for TNO155 plus spartalizumab combination or \> 2.5 x ULN for TNO155 plus ribociclib combination, or \> 5 x ULN for either combination if liver metastases are present.
• •3. Creatinine clearance \< 60 mL/min (calculated using Cockcroft-Gault equation).
• •9. Pregnant or breast-feeding (lactating) women.
• •10. History of severe hypersensitivity reactions to other mAbs.
• •11. Active, known or suspected autoimmune disease.
• •12. History of or current interstitial lung disease or pneumonitis grade ≥ 2.
• •13. Human Immunodeficiency Virus (HIV) infection, unless the patient is on antiviral therapy and has undetectable viral load.
• •14. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• •15. Systemic chronic steroid therapy
• •16. Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related toxicity.
• •17. Systolic Blood Pressure (SBP) \< 90 mmHg.
• •18. International Normalized Ratio (INR) \> 1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within seven days prior to the first dose of study drug).
• •19. History of HIV infection (testing not mandatory)
• •20. Currently receiving any of the following substances and cannot be discontinued seven days prior to Cycle 1 Day 1:
• •* Concomitant medications or herbal supplements, that are strong inducers or inhibitors of CYP3A4/5,
• •* Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
• •21. Previous treatment with a CDK4/6 inhibitor.
• •22. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
• •Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).