Study of ISM6331 in Participants With Advanced/Metastatic Malignant Mesothelioma or Other Solid Tumors

A Phase 1, Open-Label, Multicenter, FIH Study to Evaluate the Safety, Tolerability, Pharmacokinetics/Pharmacodynamics, and Preliminary Efficacy of ISM6331 in Participants With Advanced/Metastatic Malignant Mesothelioma or Other Solid Tumors

This is a Phase 1, open-label, multicenter, FIH study to evaluate the safety, tolerability, recommended Phase 2 dose (RP2D), PK/PD, and preliminary anti-tumor activity of ISM6331 in participants with advanced or metastatic malignant mesothelioma or other solid tumors. The study consists of two parts, a dose escalation part (Part 1) and a dose selection optimization part (Part 2).

Study Overview

• Status: Recruiting
• Conditions: Malignant Mesothelioma; Advanced Solid Tumor; Metastatic Malignant Solid Tumor
• Intervention / Treatment: Drug: ISM6331

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Qinhan Chen; Phone Number: +86 021-50831718; Email: Insilico-Clinicaltrial@insilico.ai

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Cancer Hospital Chinese Academy of Medical Sciences
  • Guangzhou, China
    • Recruiting
    • Sun Yat-sen University Cancer Center
  • Henan
    • Zhengzhou, Henan, China
      • Recruiting
      • Henan Cancer Hospital
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China
      • Not yet recruiting
      • Shanghai Pulmonary Hospital
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Recruiting
      • Sarah Cannon Research Institute at HealthONE
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • The University of Chicago Medical Center - Duchossois Center for Advanced Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania - Abramson Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • SCRI Oncology Partners
  • Texas
    • Austin, Texas, United States, 78758
      • Recruiting
      • NEXT Oncology - Austin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female participants with age ≥18 years at the time of signing the informed consent.
2. Histologically confirmed unresectable advanced or metastatic malignant mesothelioma or other solid tumors, who have failed standard therapy or for whom no effective standard therapy exists, participants for part 1 is regardless of the presence or absence of the genetic alterations of the Hippo pathway, but for part 2 participants with solid tumors other than mesothelioma, genetic testing documentation must demonstrate Hippo signaling pathway dysregulation.
3. Participants with malignant mesothelioma must have prior exposure to at least immune checkpoint therapy and platinum-based chemotherapy.
4. Presence of at least one evaluable lesion in Part 1 or one measurable target lesion in Part 2 according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for participants with non-pleural mesothelioma or other solid tumors and modified RECIST (mRECIST) v1.1 for participants with malignant pleural mesothelioma.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
6. Life expectancy of ≥12 weeks as judged by the investigator.
7. Adequate organ function as determined by medical assessment (within 7 days prior to the first dose of study treatment).
8. Capable of providing signed informed consent form (ICF) and complying with the requirements and restrictions listed in the ICF and in this study protocol.

Exclusion Criteria:

1. Participants who have previously received a TEAD inhibitor.
2. Participation in other therapeutic clinical studies within 28 days or 5 half-lives (whichever is shorter) prior to first dose of study treatment.
3. Anti-tumor therapy within 28 days or 5 half-lives (whichever is shorter) prior to first dose of study treatment.
4. Known active central nervous system (CNS) primary tumor or untreated CNS metastases.
5. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases.
6. Unwillingness or unable to comply with the requirements of oral drug administration, or presence of a gastro-intestinal condition
7. Have prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, laboratory abnormality or any other conditions that, in the investigator's opinion, would not be in the best interest of the participant; or that could alter the absorption, distribution, metabolism, or excretion of the study treatment; or impair the assessment of study result.
8. Currently receiving any of Strong inhibitors or inducers of P-gp, or Sensitive substrates of P-gp, CYP1A2, CYP2B6, and CYP3A4 that cannot be discontinued 14 days or 5 half-lives for inhibitors or substrates (whichever is shorter) prior to the first dose of study treatment.

Other protocol inclusion and exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Dose Escalation; Patients will receive ISM6331 once daily in sequential cohorts of increasing doses.	Drug: ISM6331; Dosage form: Capsule for oral administration. Frequency of administration: Once daily overall of treatment.
Experimental: Part 2 Dose Selection Optimization; Participants will receive ISM6331 once daily at each dose level from the two dose levels recommended by Study Review Committee.	Drug: ISM6331; Dosage form: Capsule for oral administration. Frequency of administration: Once daily overall of treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicity (DLT).	DLT is defined as any adverse event which meets DLT criteria unless it is clearly related to disease progression or intercurrent illness during the first 31 days after the initiation of treatment in the dose escalation part (Part 1).	Day 1 up to Day 31
Incidence and severity of adverse events (AEs)	Adverse events are assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [NCI CTCAE v5.0]	Approximately 12 months.
Incidence of clinically significant abnormalities in laboratory values, vital signs, physical examination, and electrocardiogram (ECG) measurements.	Regular monitoring and assessment of vital signs (pulse rate, blood pressure, respiratory rate, and temperature), physical examinations, laboratory values, ECG, and other safety examinations by investigators.	Approximately 12 months.
Recommended Phase 2 Dose (RP2D)	The RP2D will be recommended by safety review committee (SRC) upon reviewing all available safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary efficacy data from Part 1 and Part 2.	Approximately 40 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed concentration (Cmax)	Pharmacokinetics (PK) parameters of ISM6331 after dose of ISM6331 will be assessed.	Approximately 12 months
Area under the concentration-time curve (AUC)	Pharmacokinetics (PK) parameters of ISM6331 after dose of ISM6331 will be assessed.	Approximately 12 months
Terminal half-life (t1/2)	Pharmacokinetics (PK) parameters of ISM6331 after dose of ISM6331 will be assessed.	Approximately 12 months
Objective response rate (ORR).	Efficacy assessments will be conducted at baseline and every 8 weeks within the first 6 months after the first dose of study treatment, then every 12 weeks thereafter, until progressive disease confirmed by the investigator, start of a new anti-tumor treatment, death, lost to follow-up, or withdrawal from the study, whichever occurs first.	Approximately 12 months
Best objective response (BOR).	Efficacy assessments will be conducted at baseline and every 8 weeks within the first 6 months after the first dose of study treatment, then every 12 weeks thereafter, until progressive disease confirmed by the investigator, start of a new anti-tumor treatment, death, lost to follow-up, or withdrawal from the study, whichever occurs first.	Approximately 12 months
Duration of response (DoR).	Efficacy assessments will be conducted at baseline and every 8 weeks within the first 6 months after the first dose of study treatment, then every 12 weeks thereafter, until progressive disease confirmed by the investigator, start of a new anti-tumor treatment, death, lost to follow-up, or withdrawal from the study, whichever occurs first.	Approximately 12 months

Collaborators and Investigators

• Sponsor: InSilico Medicine Hong Kong Limited

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2024
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): February 28, 2028

Study Registration Dates

• First Submitted: August 13, 2024
• First Submitted That Met QC Criteria: August 19, 2024
• First Posted (Actual): August 22, 2024

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 12, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Hippo pathway; Transcriptional enhanced associate domain (TEAD); TEAD inhibitor; ISM6331; YAP/TAZ-TEAD
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Pathological Conditions, Signs and Symptoms; Mesothelioma; Mesothelioma, Malignant; Neoplasm Metastasis
• Other Study ID Numbers: ISM6331-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No