Study of ISM3412 in Participants With Locally Advanced/Metastatic Solid Tumors

A Phase 1, Open-Label, Multicenter, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics/Pharmacodynamics, and Preliminary Efficacy of ISM3412 in Participants With Locally Advanced/Metastatic Solid Tumors

The study has consists of two parts, a dose escalation part (Part 1) and a dose selection optimization part (Part 2). The primary objectives of this study are to evaluate the safety and tolerability of ISM3412 in participants with locally advanced/metastatic solid tumors, and to determine the RP2D of ISM3412.

Study Overview

• Status: Not yet recruiting
• Conditions: Locally Advanced/Metastatic Solid Tumors
• Intervention / Treatment: Drug: ISM3412

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 1

Contacts and Locations

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

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 locally advanced or metastatic solid tumors with confirmed homozygous MTAP deletion, who have disease progression after standard therapy, intolerable to standard therapy, or for whom no standard therapy exists.
3. Have measurable or evaluable lesions in Part 1 and at least one measurable target lesion in Part 2 as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
4. Participants must provide a documentary evidence of homozygous MTAP deletion; or provide archival formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks or at least 15 FFPE tumor tissue slides, or perform tumor tissue biopsies for a confirmatory genetic test indicating homozygous MTAP deletion.
5. ECOG PS (Eastern Cooperative Oncology Group Performance Status) ≤1.
6. Life expectancy of ≥12 weeks as judged by the investigator.
7. Adequate organ function as determined by medical assessment.
8. Capable of providing signed ICF and complying with the requirements and restrictions listed in the ICF and in this study protocol.

Exclusion Criteria:

1. Prior treated with other MAT2A inhibitors and/or PRMT inhibitors.
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 (chemotherapy, immunotherapy, hormonal therapy, targeted therapy, biologic therapy, or other anti-tumor therapy, except for hormones for hypothyroidism or estrogen replacement therapy, anti-estrogen analogues, agonists required to suppress serum testosterone levels) within 28 days or 5 half-lives, whichever is shorter prior to first dose of study treatment.
4. Toxicities of prior therapy have not resolved to Grade ≤1 or to baseline (as evaluated by NCI CTCAE version 5.0)
5. History of another primary tumor that has been diagnosed or required therapy within the past 3 years.
6. Previous history of, or presence of Gilbert's syndrome.
7. Previous history of myelodysplastic syndrome.
8. Prior solid organ or hematopoietic stem cell transplant.
9. Known active central nervous system (CNS) primary tumor or untreated CNS metastases.
10. Have serious cardiovascular or cerebrovascular disease as per protocol.
11. Presence of uncontrolled systemic infection as per protocol.
12. Unwillingness or unable to comply with the requirements of oral drug administration, or presence of a gastro-intestinal condition.

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 ISM3412 once daily in sequential cohorts of increasing doses.	Drug: ISM3412; ISM3412 will be administered orally once daily.
Experimental: Part 2 Dose Selection Optimization; Participants will be randomized to receive one of the two selected dose levels of ISM3412 once daily determined by Study Review Committee.	Drug: ISM3412; ISM3412 will be administered orally once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicity (DLT) events	To evaluate the safety and tolerability of ISM3412.	31 days
Incidence and severity of adverse events (AEs)	To evaluate the safety and tolerability of ISM3412.	Approximately 30 months
Recommended phase 2 dose (RP2D)	To determine the RP2D of ISM3412.	Approximately 30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed concentration (Cmax)	To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412	Approximately 30 months
Time of maximum observed concentration (Tmax)	To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412	Approximately 30 months
Area under the concentration-time curve (AUC)	To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412	Approximately 30 months
Terminal half-life (t1/2)	To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412	Approximately 30 months
Objective response rate (ORR)	To evaluate the preliminary efficacy of ISM3412 in participants with locally advanced/metastatic solid tumors.	Approximately 30 months
Best objective response (BOR)	To evaluate the preliminary efficacy of ISM3412 in participants with locally advanced/metastatic solid tumors.	Approximately 30 months
Duration of response (DoR)	To evaluate the preliminary efficacy of ISM3412 in participants with locally advanced/metastatic solid tumors.	Approximately 30 months

Collaborators and Investigators

• Sponsor: InSilico Medicine Hong Kong Limited

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: May 7, 2024
• First Submitted That Met QC Criteria: May 9, 2024
• First Posted (Actual): May 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 14, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: MAT2A inhibitor; Methionine adenosyltransferase 2A (MAT2A); homozygous MTAP deletion; ISM3412
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: ISM3412-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No