Study of TYK-01054 Capsules in Patients With Advanced Solid Tumors

Dose Escalation (Part A) will employ an accelerated titration design combined with a "3 + 3" design to evaluate the safety and pharmacokinetic (PK) profile of TYK-01054 in patients with mesothelioma and/or metastatic solid tumors who are resistant to standard therapy or for which no effective standard therapy is available. Dose escalation phase comprises a single-dose stage (7 days) and a continuous dosing stage. Accelerated titration will switch to the conventional 3+3 design as soon as any patient experiences a ≥Grade 2 TYK-01054-related toxicity or when the second patient at any dose level completes the first cycle without dose-limiting toxicity (DLT). Dose escalation will continue until the Maximum Tolerated Dose (MTD), Recommended Dose for Expansion (RDE), or a suitable intermittent dosing regimen is determined. The RDE(s) selected in Part A will be carried forward into the dose optimisation phase.

Dose Optimization (Part B) will further assess safety and PK, and will evaluate preliminary anti-tumor activity at two RDE levels. Approximately 40 patients with four target indications will be enrolled and randomised 1:1 to receive either RDE or RDE-1. Based on PK, safety, and all cumulative data, the Study Review Committee (SRC) will determine the dose for the Part c (i.e., the Recommended Phase 2 Dose, RP2D).

Cohort Expansion (Part C) includes four cohorts.

• Cohort 1: Advanced (unresectable or metastatic) malignant mesothelioma(MM); regardless of NF2 mutation status or other Hippo pathway abnormalities.
• Cohort 2: Advanced (unresectable or metastatic) Small-cell lung cancer (SCLC) that has progressed after first-line therapy.
• Cohort 3: Advanced (unresectable or metastatic) Head-and-neck squamous-cell carcinoma (HNSCC) that has progressed after first-line systemic therapy.
• Cohort 4: Advanced (unresectable or metastatic) solid tumours; priority will be given to colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), non-small-cell lung cancer (NSCLC), and epithelioid haemangioendothelioma (EHE).

Cohorts 2-4 require that patients also have abnormalities in the Hippo signaling pathway, NF2, MST1/2, LATS1/2, FAT1 mutations/alterations or YAP/TAZ fusion.

Inclusion criteria

• Male or female subjects ≥18 years old
• Histologically or cytologically confirmed incurable, locally advanced or metastatic advanced solid tumors. All participants are required to provide results of Hippo signaling pathway gene testing; however, this requirement is not a mandatory inclusion criterion for Dose Escalation (Part A) and EHE patients.
• Advanced solid tumors must have progressed after receiving at least one standard first-line anti-tumor therapy, OR demonstrate intolerance to standard therapy, OR Lack of standard treatment.
• Patients should have at least 1 measurable lesion as per RECIST v1.1 or mRECIST v1.1.
• Adequate organ function, including hepatic, renal, cardiovascular, astrointestinal,respiratory, and hematopoietic systems.
• ECOG 0-1，
• Life expectancy of >3 months.
• Willing and able to comply with all aspects of the protocol.

Exclusion criteria

• History of other malignancy, except for:

Non-melanoma skin cancer (basal cell carcinoma or squamous cell carcinoma) that is non-invasive and has been effectively controlled with no recurrence or metastasis for 5 years, Papillary thyroid carcinoma, Carcinoma in situ of the cervix, Ductal carcinoma in situ of the breast.

• Unstable brain metastases,such as:

Patients requiring urgent neurosurgical intervention for CNS complications, Presence of symptomatic spinal cord compression due to tumor, Presence of leptomeningeal disease (carcinomatous meningitis).

• Presence of pleural effusion, pericardial effusion, or ascites that, in the investigator's judgment, cannot be stably controlled by repeated drainage or other methods.
• Clinically significant renal disease.
• Clinically significant cardiovascular disease, including but not limited to myocardial infarction, unstable angina, congestive heart failure (NYHA Class ≥ II), or uncontrolled arrhythmias.
• Patients with uncontrolled infectious diseases, such as immunodeficiency disorders (e.g., HIV) or active hepatitis B or C infection; chronic hepatitis B or C carriers without symptoms are excluded from this criterion.
• Known or suspected hypersensitivity to TYK-01054 or any of its excipients, or to compounds of similar chemical class.
• Patients who have previously received a TEAD inhibitor.
• Women who are pregnant or breastfeeding.