TT-4 and TT-10 as Single Agents and in Combination in Subjects With Advanced Selected Solid Tumors and Pleural Mesothelioma

Exclusion criteria

• ✕Participants will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:
• ✕Participants are to be excluded from the study if they meet any of the following criteria:
• ✕1. Major surgery within 4 weeks prior to Screening
• ✕2. Participants with active CNS metastases are excluded.
• ✕a. Participants with treated CNS metastases are eligible provided all of the following are met: i. Definitive local therapy completed (surgery and/or radiotherapy, including SRS or WBRT) ≥4 weeks before first dose; ii. Neurologically stable (no new/worsening neurologic signs/symptoms attributable to CNS disease) for ≥2 weeks prior to first dose; iii. No evidence of progression of CNS lesions on screening brain MRI (baseline MRI required at Screening); iv. Off corticosteroids, or on a stable/decreasing dose not exceeding ≤10 mg prednisone equivalent/day for ≥7 days prior to first dose (physiologic replacement permitted); v. No leptomeningeal metastases (LMD excluded). b. Leptomeningeal metastases are not eligible.
• ✕3. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• ✕4. Prior anti-cancer therapy within 4 weeks prior to the start of study intervention. A 2 week washout is acceptable for short-acting drugs (e.g., tyrosine kinase inhibitors). Any treatment-related toxicities must be resolved to Grade 0 - 1.
• ✕5. Human immunodeficiency virus (HIV)-infected participants
• ✕6. Participants who are hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment (Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention). Hepatitis B screening tests are not required unless:
• ✕1. Known history of HBV infection
• ✕2. As mandated by local health authority
• ✕7. Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening. Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to enrollment. Hepatitis C screening tests are not required unless:
• ✕1. Known history of HCV infection
• ✕2. As mandated by local health authority
• ✕8. Participants requiring immunosuppressive therapy: Participants who require systemic immunosuppressive therapy at Screening or within 14 days prior to first dose are excluded. Systemic immunosuppressive therapy includes, but is not limited to, chronic corticosteroids at \>10 mg/day prednisone equivalent, and other systemic immunosuppressants or biologic agents (e.g., cyclosporine, mycophenolate, azathioprine, methotrexate, TNF inhibitors such as adalimumab/infliximab, vedolizumab, JAK inhibitors such as tofacitinib, dupilumab, rituximab, or similar agents).
• ✕a. Permitted exceptions: i. Physiologic corticosteroid replacement for documented adrenal insufficiency (e.g., hydrocortisone replacement) is permitted.
• ✕ii. Inhaled, intranasal, topical steroids, and short courses of systemic steroids for non-immune indications (e.g., premedication for imaging contrast, antiemetic prophylaxis) may be permitted at the Investigator's discretion.
• ✕iii. Local steroid injections (e.g., intra-articular) may be permitted if not expected to result in systemic immunosuppression.
• ✕b. Washout: A minimum 14-day washout from systemic immunosuppressive therapy prior to first dose may be permitted based on Investigator judgment and Medical Monitor approval, provided the underlying condition is stable and the participant does not require ongoing immunosuppression.
• ✕9. Participants requiring administration of drugs known to be strong inhibitors or inducers of CYP3A4, 2C9 or 2C19
• ✕10. Participants requiring drugs that modify gastric pH, such as proton-pump inhibitors (PPIs) or H2 blockers. Antacids, such as calcium carbonate or aluminum hydroxide-based products, will be allowed during the study, but are recommended to be taken either 4 hours before or 2 hours after dosing of TT-10 or TT-4 Diacid.
• ✕11. Ongoing systemic bacterial, fungal or viral infections at Screening Note: Participants on antimicrobial, antifungal or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met
• ✕12. Administration of a live vaccine within 6 weeks of first dose of study intervention. Messenger ribonucleic acid (mRNA) vaccines for the prevention of Coronavirus Disease 2019 (COVID-19) infection are permitted.
• ✕13. Baseline QT interval corrected with Fridericia's method (QTcF) \>470 ms (average of triplicate readings) Note: Criterion does not apply to participants with a right or left bundle branch block.
• ✕14. Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy)
• ✕15. Female participants who are pregnant or breastfeeding
• ✕16. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix or prostate intraepithelial neoplasia
• ✕17. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
• ✕18. History of peptic ulcer and/or gastrointestinal bleed within the past 6 months prior to Screening
• ✕19. History of stroke, unstable angina, myocardial infarction or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to Screening
• ✕20. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes), current evidence of uncontrolled hypertension despite optimal medical management at screening, or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the participant associated with his or her participation in the study