A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of INV-8989 in Patients With Advanced Solid Tumors Harboring KRAS G12D Mutations

A Phase I/II, Open-Label, Multi-Center, Dose Escalation and Cohort Expansion Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of INV-8989 in Patients With Advanced Solid Tumors Harboring KRAS G12D Mutations

This is a Phase 1 and Phase 2 study to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of INV-8989 in patients with advanced solid tumors harboring KRAS G12D mutations.

This is a Phase 1 and Phase 2 study to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of INV-8989 in patients with advanced solid tumors harboring KRAS G12D mutations.

The entire study consists of two parts: Phase 1 for dose escalation and Phase 2 for dose expansion and indication exploration.

Phase 1 dose escalation of INV-8989 follows a real time monitored, PK/PD and safety guided scheme with an accelerated titration plus traditional 3+3 design for DLT assessment.

Phase 2 aims to reassure the safety profile and better define efficacy. Phase 2 consists of Phase 2a and Phase 2b.

Phase 2a study aims to further confirm the safety profile of INV-8989 through a larger number of patients, clarify its PK characteristics and preliminary efficacy, and optimize the recommended Phase 2 dose (RP2D).

The Phase 2b study aims to explore the anti-tumor efficacy of INV-8989 in the patients with different types of advanced solid tumors harboring the KRAS G12D mutation, and those who have failed previous standard treatments.

Inclusion Criteria:

1. Written informed consent obtained.
2. Adult patients aged ≥ 18 years.
3. Patients with histologically or cytologically confirmed locally advanced, unresectable, or metastatic solid tumors harboring the KRAS G12D mutations.
4. Agree to provide available archived FFPE tumor tissue specimens or voluntarily accept pre-treatment tumor biopsy.
5. Have RECIST 1.1-defined measurable lesions.
6. Has a life expectancy of > 3 months.
7. ECOG performance status 0-1.
8. Adequate marrow, liver and kidney function.
9. Meet the study's specified contraceptive requirements.
10. Meet protocol-specified washout period requirements.

Exclusion Criteria:

1. Have protocol-defined toxicities within 28 days before the start of study treatment.
2. Have a second primary malignancy.
3. Patients with known hypersensitivity to the study drug or any of its components.
4. Prior history of receiving targeted therapy with specific KRAS G12D inhibitors/degraders or pan-RAS inhibitors/degraders for KRAS G12D mutation.
5. Has undergone major surgery within 28 days prior to the first dose of study drug.
6. Patients with symptomatic brain or leptomeningeal metastases.
7. Patients with other severe and persistent underlying medical conditions as assessed by the Investigator.
8. Have protocol-defined clinically significant cardiovascular diseases.
9. Prolonged QTcF interval.
10. Patients with dyspnea at rest secondary to complications of advanced malignancy, or requiring continuous oxygen therapy due to other medical conditions.
11. Patients with active pulmonary tuberculosis (TB).
12. Patients with a known history of interstitial lung disease (ILD).
13. Patients with a known history of allogeneic solid organ transplantation or allogeneic hematopoietic stem cell transplantation.
14. Have experienced a severe concurrent infection within 28 days prior to the first dose of study drug.
15. Patients with congenital or acquired immunodeficiency.
16. Female patients in pregnancy or lactation period.
17. Patients with concomitant diseases or conditions deemed by the Investigator likely to interfere with protocol compliance.
18. Patients unwilling or unable to comply with protocol-specified procedures.