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

Official title

A Phase I/II, Open-label, Multicenter Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of the TEAD Inhibitor TYK-01054 Capsules in Patients With Locally Advanced or Metastatic Advanced Solid Tumors

Overview

This study is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the TEAD inhibitor TYK-01054 capsules in patients with locally advanced or metastatic advanced solid tumors

Detailed description

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.

Interventions

• Drug TYK-01054
  TKY-01054 will be administered orally at a starting dose of 25 mg in 21-day cycles. If well tolerated, dose expansion will proceed in the recommended dose for expansion (RDE) and RDE-1 until the recommended Phase II dose (RP2D) is determined.

Primary outcome measures

• Dose Limiting Toxicity [Time frame: Up to approximately 28 days]
• Maximum tolerated dose（MTD） [Time frame: Through the Dose Escalation phase, approximately 12 months]
• Number of participants who experience one or more adverse events (AEs) [Time frame: From Baseline up to 28 days after the end of the treatment]
• Recommended Dose for Expansion(RDE) [Time frame: Through the Dose Escalation Phase, approximately 24 months]
• Recommended Phase 2 Dose（RP2D） [Time frame: Within 28 days of the last patient dosed in the Dose Optimization stage]

Secondary outcome measures (2)

• Evaluate the pharmacokinetics of TYK-01054 [Time frame: Through the Dose Escalation stage and Dose Optimization stage, approximately 24 month]
• Evaluate the effectiveness of TYK-01054 [Time frame: Approximately 36 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Shanghai Chest Hospital — Shanghai

Identifiers

NCT: NCT07282873 · TYKM1408101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗