NSCLC Stage IV, KRAS G12C
Conditions
Brief summary
This study evaluates the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) of Glecirasib in combination with Ivonescimab in patients with previously untreated, KRAS G12C-mutated, locally advanced or metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥1%. The study includes a Phase I 3+3 dose-escalation stage followed by a Phase II Simon two-stage design to assess preliminary antitumor efficacy.
Interventions
DRUGGlecirasib
For Phase I Dose Escalation, Glecirasib includes 2 dose cohorts: 600 mg QD and 800 mg QD, respectively, to determine the Glecirasib PR2D dose for the Phase II study.
DRUGIvonescimab
Administered intravenously at 20 mg/kg, every 3 weeks (Q3W).
Sponsors
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed written informed consent. * Age ≥18 years. * Newly diagnosed, unresectable, locally advanced (ineligible for curative concurrent - chemoradiotherapy) or metastatic NSCLC per AJCC 9th edition. * KRAS G12C mutation confirmed by validated testing. * PD-L1 TPS ≥1%. * ≥1 measurable lesion per RECIST v1.1. * No prior systemic therapy for advanced/metastatic NSCLC; prior adjuvant therapy allowed if completed \>6 months before dosing and toxicities recovered to ≤Grade 1. * ECOG PS 0-2. * Life expectancy \>3 months * Adequate organ function (hematologic, hepatic, renal, coagulation per protocol thresholds) * Negative pregnancy test for women of childbearing potential; adequate contraception for men and women through 3 months post-treatment * Willing and able to comply with study procedures and follow-up.
Exclusion criteria
* History of other malignancies (exceptions: cured basal cell carcinoma, cervical carcinoma in situ) * Predominant squamous NSCLC, small cell carcinoma, or neuroendocrine carcinoma. * Other actionable drivers (EGFR, ALK, ROS1, RET, BRAF, NTRK, MET, etc.). * Known hypersensitivity to study drugs. * Prior PD-1/PD-L1 inhibitors or KRAS inhibitors. * Active autoimmune disease or autoimmune disease history requiring systemic therapy. * Systemic immunosuppressive therapy within 14 days prior to first dose. * Symptomatic ascites/pleural effusion needing recurrent drainage. * Significant cardiovascular disease (NYHA ≥2, MI within 1 year, uncontrolled arrhythmias). * Active infection, unexplained fever \>38.5°C. * Interstitial lung disease or pneumonitis. * HIV infection or other immunodeficiency. * Live vaccines within 4 weeks. * Substance abuse, alcoholism, or psychiatric disorders impairing compliance. * Unable to swallow oral medication. * Any condition that may interfere with study participation or interpretation as judged by investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose (MTD) | 21 days after the first dose. | The MTD is determined using a standard 3+3 dose-escalation design. It is defined as the dose level prior to the dose at which ≥2 out of 3-6 patients experience a Dose-Limiting Toxicity (DLT) within the first 21 days of treatment |
| Phase I: Incidence of Dose-Limiting Toxicities (DLTs) | 21 days after the first dose. | Evaluation of toxicities related to the study drugs, including hematologic and non-hematologic toxicities as defined in the protocol. |
| Phase I: Recommended Phase 2 Dose (RP2D) | 21 days after the first dose. | The RP2D of Glecirasib in combination with Ivonescimab will be selected based on the comprehensive evaluation of the MTD, DLT occurrences, and overall safety data observed during the Phase I escalation phase. This dose will then be utilized in the Phase II Simon's two-stage expansion to further evaluate efficacy and safety. |
| Phase II: Objective Response Rate (ORR) | Assessed up to 24 months | The proportion of patients who achieve a Complete Response (CR) or Partial Response (PR) based on RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Up to 24 months | Proportion of patients with CR, PR, or SD. |
| Incidence of Adverse Events (AEs) | From first dose enrollment through 28 days after the last dose. | Severity of AEs graded by CTCAE v5.0 |
| Progression-Free Survival (PFS) | Up to 24 months | Time from the first dose to the first documented disease progression or death from any cause. |
| Duration of Response (DOR) | Up to 24 months | Time from the first documented response (CR or PR) to progression or death. |
| Overall Survival (OS) | Up to 24 months | Time from the first dose to death from any cause |
Contacts
Primary ContactZhijie Wang, MD
Outcome results
None listed