## Protocol Section
### Identification Module
**NCT ID:** NCT06414460

**Brief Title:** Study of ISM3412 in Participants With Locally Advanced/Metastatic Solid Tumors

**Official Title:** 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

#### Organization Study ID Info
**ID:** ISM3412-101
#### Organization
**Class:** INDUSTRY
**Full Name:** InSilico Medicine Hong Kong Limited
### Status Module
#### Completion Date
**Date:** 2029-03-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-16

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-14

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2028-03-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2025-03-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-16
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-07
**Study First Submit QC Date:** 2024-05-09
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** InSilico Medicine Hong Kong Limited

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** 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.

### Conditions Module

**Conditions:**

- Locally Advanced/Metastatic Solid Tumors

**Keywords:**

- Methionine adenosyltransferase 2A (MAT2A)

- homozygous MTAP deletion

- MAT2A inhibitor

- ISM3412

### Design Module

#### Design Info

**Allocation:** NON_RANDOMIZED

**Intervention Model:** SEQUENTIAL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 80

**Type:** ESTIMATED

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients will receive ISM3412 once daily in sequential cohorts of increasing doses.

**Intervention Names:**

- Drug: ISM3412

**Label:** Part 1 Dose Escalation

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Participants will be randomized to receive one of the two selected dose levels of ISM3412 once daily determined by Study Review Committee.

**Intervention Names:**

- Drug: ISM3412

**Label:** Part 2 Dose Selection Optimization

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Part 1 Dose Escalation

- Part 2 Dose Selection Optimization

**Description:** ISM3412 will be administered orally once daily.

**Name:** ISM3412

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** To evaluate the safety and tolerability of ISM3412.

**Measure:** Incidence of dose-limiting toxicity (DLT) events

**Time Frame:** 31 days

**Description:** To evaluate the safety and tolerability of ISM3412.

**Measure:** Incidence and severity of adverse events (AEs)

**Time Frame:** Approximately 30 months

**Description:** To determine the RP2D of ISM3412.

**Measure:** Recommended phase 2 dose (RP2D)

**Time Frame:** Approximately 30 months

#### Secondary Outcomes

**Description:** To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412

**Measure:** Maximum observed concentration (Cmax)

**Time Frame:** Approximately 30 months

**Description:** To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412

**Measure:** Time of maximum observed concentration (Tmax)

**Time Frame:** Approximately 30 months

**Description:** To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412

**Measure:** Area under the concentration-time curve (AUC)

**Time Frame:** Approximately 30 months

**Description:** To assess PK of ISM3412 in plasma following a single and multiple doses of ISM3412

**Measure:** Terminal half-life (t1/2)

**Time Frame:** Approximately 30 months

**Description:** To evaluate the preliminary efficacy of ISM3412 in participants with locally advanced/metastatic solid tumors.

**Measure:** Objective response rate (ORR)

**Time Frame:** Approximately 30 months

**Description:** To evaluate the preliminary efficacy of ISM3412 in participants with locally advanced/metastatic solid tumors.

**Measure:** Best objective response (BOR)

**Time Frame:** Approximately 30 months

**Description:** To evaluate the preliminary efficacy of ISM3412 in participants with locally advanced/metastatic solid tumors.

**Measure:** Duration of response (DoR)

**Time Frame:** Approximately 30 months

### Eligibility Module

**Eligibility Criteria:** 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.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** Insilico-Clinicaltrial@insilico.ai

**Name:** Yichen Liu

**Phone:** +86 021-50831718

**Role:** CONTACT

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Meshes

- ID: D000009369

- Term: Neoplasms

### Intervention Browse Module - Browse Branches

- Abbrev: AA

- Name: Amino Acids

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: T12

- Name: Methionine

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
