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

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

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

Exclusion criteria

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