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

Phase 2RecruitingNCT07610798

Shenzhen Ionova Life Sciences Co., Ltd.178 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

178

Conditions

Advance Solid Tumors

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Phase 1: Number of participants with treatment-emergent adverse events (TEAEs) as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

The number and percentage of participants with at least one TEAE will be summarized by severity grade and relationship to study drug.

Time frame: 12 months

Phase 1: Maximum tolerated dose (MTD)

The highest dose level at which at least 6 patients have been treated and less than 33% of patients experienced a DLT.

Time frame: Within first 21 days of treatment

Phase 1: Recommended dose range (RDR) and/or Recommended Phase Ⅱ dose (RP2D)

The RDR and/or RP2D will be determined based on the PK and PD data, the preliminary clinical activity of INV-8989, as well as the incidence rate and nature of the toxicities observed in subsequent cycles beyond Cycle 1.

Time frame: 12 months

Phase 2: Evaluate overall response rate (ORR)

To evaluate ORR per RECIST v1.1

Time frame: 12 months

Secondary Outcomes

Phase 1: Determine the pharmacokinetics (PK) using AUC of INV-8989

To determine the (PK) using AUC of INV-8989 after a single dose and at steady state after multiple doses

Time frame: 12 months

Phase 1: Determine the PK using Cmax of INV-8989

Determine the PK using Cmax of INV-8989 after a single dose and at steady state after multiple doses

Time frame: 12 months

Phase 1: Evaluate overall response rate (ORR)

To evaluate ORR per RECIST v1.1

Time frame: 12 months

Phase 1: Evaluate progression free survival (PFS)

To evaluate PFS per RECIST v1.1

Time frame: 12 months

Phase 2: Evaluate progression free survival (PFS)

To evaluate PFS per RECIST v1.1

Time frame: 12 months

Phase 2: Determine the PK using AUC of INV-8989

Determine the PK using AUC of INV-8989 after a single dose and at steady state after multiple doses

Time frame: 12 months

Phase 2: Determine the PK using Cmax of INV-8989

To determine the PK using Cmax of INV-8989 after a single dose and at steady state after multiple doses

Time frame: 12 months

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts