KRAS G12D Mutation, NSCLC (Non-small Cell Lung Cancer)
Conditions
Keywords
GFH375, Docetaxel, Non-small cell lung cancer (NSCLC), KRAS G12D
Brief summary
The purpose of this study is to compare the effectiveness, safety and tolerability of GFH375 versus docetaxel in participants with KRAS G12D-mutant non-small cell lung cancer (NSCLC). GFH375 is an oral, highly selective, non-covalent small-molecule inhibitor targeting the KRAS G12D mutation. Preclinical studies showed GFH375 strongly blocks KRAS-driven signaling and cancer cell growth, and demonstrated anti-tumor activity in NSCLC animal models. Docetaxel is a chemotherapy drug for locally advanced or metastatic NSCLC. This is an open-label, randomized controlled trial. Both participant and study doctor will know which study medication each participant receives. After enrollment, participant will be randomly assigned to either the GFH375 group or docetaxel group by chance. Neither participant nor study doctor can pick your treatment group. You have a two-thirds chance to receive GFH375 and a one-third chance to receive docetaxel. * GFH375 group: Take GFH375 tablets by mouth once daily as scheduled; each treatment cycle lasts 21 days. * Docetaxel group: Receive docetaxel via intravenous infusion at 75 mg/m² once every 3 weeks. Study treatment will continue until cancer gets worse, participant can't tolerate the study treatment, or other conditions make participant unable to keep receiving study treatment. Some participants on docetaxel may be able to switch to GFH375 during the study if their cancer becomes worse. There will be safety checks at each visit, and the doctors will continue to check for medical problems and participant 's wellbeing throughout the study. Participants will continue to have scans of their tumor every 6 weeks for the first year, then every 9 weeks until their cancer becomes worse. After participant's cancer becomes worse, clinic staff will telephone participant every 3 mouths to check on their cancer.
Interventions
DRUGGFH375
GFH375 administered orally at the protocol-specified dose once daily. Each treatment cycle is 21 days.
DRUGDocetaxel
Receive docetaxel via intravenous infusion at 75 mg/m² once every 3 weeks.
Sponsors
Genfleet Therapeutics (Shanghai) Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Voluntary participation in the study and signed informed consent form (ICF). * 2\. Age ≥ 18 years at the time of signing the ICF; male or female. * 3\. Histologically or cytologically confirmed locally advanced unresectable or metastatic non small cell lung cancer (NSCLC). * 4\. Participants must provide adequate and qualified tumor tissue slides samples or agree to undergo tumor biopsy to obtain tissue samples for central laboratory confirmation of KRAS G12D mutation. * 5\. Disease progression or intolerance to toxicity after at least one prior line of platinum based chemotherapy and anti PD 1/PD L1 antibody therapy. * 6\. At least one measurable target lesion according to RECIST version 1.1. * 7\. Investigator assessed life expectancy ≥ 12 weeks. * 8\. Adequate organ function. * 9\. Ability to communicate well, comply with scheduled follow up visits, and adhere to protocol requirements.
Exclusion criteria
* 1\. Presence of other driver gene mutations in NSCLC, or concurrent other KRAS or RAS mutations. * 2\. Other malignancy that has progressed or required treatment within 3 years prior to randomization. * 3\. Leptomeningeal metastasis, or symptomatic or progressive central nervous system (CNS) metastasis. * 4\. Existing or potential severe bone injury due to bone metastasis, or uncontrolled pain related to bone metastasis. * 5\. Prior treatment with KRAS G12D targeted therapy or pan RAS/KRAS targeted therapy. * 6\. Prior treatment with docetaxel as part of systemic therapy. * 7\. Radiotherapy within 4 weeks prior to randomization, or other local anti tumor therapy within 4 weeks prior to randomization. * 8\. Other anti tumor therapy within 28 days or 5 half lives prior to randomization, or cell therapy within 3 months prior to randomization. * 9\. Clinically significant severe cardiovascular disease. * 10\. Stroke or other severe cerebrovascular disease within 6 months prior to randomization. * 11\. Major acute or chronic infectious disease. * 12\. Other poorly controlled systemic diseases. * 13\. Severe psychiatric or psychological disorder, or history of drug abuse, or severe alcohol abuse. * 14\. Pregnancy or breastfeeding. * 15\. Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate(ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR) | From the first dose until the date of first documented CR or PR, assessed up to 24 months | ORR is the proportion of participants whose best response is either complete response (CR) or partial response (PR) per RECIST v1.1 assessed by BICR. |
| Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR) | From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. | PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1, as assessed by BICR or until death due to any cause, whichever comes first. |
| Overall Survival (OS) | From the first dose until the date of death from any cause, whichever came first, assessed up to 36~48 months | OS is defined as the time from the date of randomization until the date of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) per RECIST v1.1, as assessed by the investigator | From the first dose until the date of first documented CR or PR,assessed up to 24 months. | ORR is defined as the proportion of participants whose best overall response (BOR) is rated as confirmed complete response (CR) or confirmed partial response (PR) per RECIST v1.1. as assessed by the investigator. |
| PFS per RECIST v1.1. as assessed by the investigator | From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. | PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1 as assessed by the investigator or until death due to any cause, whichever comes first. |
| DCR per RECIST v 1.1 as assessed by the investigator and the BICR | From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. | DCR is defined as the proportion of participants whose best overall response is rated as CR, confirmed PR or SD per RECIST v1.1 as assessed by the investigator and the BICR. |
| DoR per RECIST v 1.1 as assessed by the investigator and the BICR | From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. | DOR is defined as the time from the date of first documented response (CR or PR subsequently confirmed) to the date of first documented PD per RECIST v1.1 as assessed by the investigator and the BICR or death due to any cause, whichever occurs first. |
| TTR per RECIST v 1.1 as assessed by the investigator and the BICR | From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. | TTR is defined as the time from the date of randomization to the first documentation of objective response (confirmed CR or confirmed PR) per RECIST v1.1. as assessed by the investigator and the BICR. |
| Number of Participants with Adverse Events (AEs) | From the first dose until 30 days after the last dose, assessed up to 24 months. | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. |
| Severity of Adverse Events(AEs) | From the first dose until 30 days after the last dose, assessed up to 24 months. | The severity of an adverse event is commonly graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE )5.0. |
| Incidence of AEs that result in treatment discontinuation, treatment interruption, or dose reduction. | From the first dose until 30 days after the last dose, assessed up to 24 months. | AEs that result in treatment discontinuation, treatment interruption, or dose reduction. |
| Severity of adverse events (AEs) leading to treatment discontinuation, treatment interruption, and dose reduction. | From the first dose until 30 days after the last dose, assessed up to 24 months. | Severity of adverse events (AEs) leading to treatment discontinuation, treatment interruption, and dose reduction per CTCAE 5.0. |
| Time to deterioration in NSCLC symptoms evaluated via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) items | From the first dose until 30 days after the last dose, assessed up to 24 months. | Time to deterioration is defined as time between randomization and the first occurrence of a meaningful deterioration in the corresponding EORTC QLQ-LC13 items score compared with the baseline score. EORTC QLQ-LC13 is a lung-cancer specific module that serves as an additional 13 item questionnaire to the general EORTC cancer questionnaire. It consists of 3 items to assess dyspnea, and 10 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Scores range from 0 to 100. A high score for a symptom scale/item represents a high level of symptomatology/problems. |
| Time to Worsening measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) items | From the first dose until 30 days after the last dose, assessed up to 24 months. | Time to Worsening is defined as time between randomization and the first occurrence of a meaningful worsening in the composite EORTC QLQ-C30 items scores compared with the baseline score. EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional scales (physical, role, emotional, social and cognitive), 9 symptom scales/items (fatigue, nausea/vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." For functional scales, higher scores indicate better functioning, while for symptom scales/items, higher scores indicate worse symptoms. |
| Change from baseline in EORTC QLQ-C30 | From the first dose to week12. | The EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional scales (physical, role, emotional, social and cognitive), 9 symptom scales/items (fatigue, nausea/vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." For functional scales, higher scores indicate better functioning, while for symptom scales/items, higher scores indicate worse symptoms. |
| Change from baseline in EORTC QLQ-LC13 | From the first dose to week12. | EORTC QLQ-LC13 is a lung-cancer specific module that serves as an additional 13 item questionnaire to the general EORTC cancer questionnaire. It consists of 3 items to assess dyspnea, and 10 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Scores range from 0 to 100. A high score for a symptom scale/item represents a high level of symptomatology/problems. |
| Pharmacokinetics (PK) of GFH375: Trough concentration after multiple dosing | From the first dose to Cycle 6 Day 1(each cycle is 21 days). | Trough concentration will be recorded from plasma samples collected. |
| PK of GFH375: Peak concentration after multiple dosing | From the first dose to Cycle 6 Day 1(each cycle is 21 days). | Peak concentration will be recorded from plasma samples collected. |
Countries
China
Contacts
CONTACTJunnan Dong
CONTACTYolanda Zeng
PRINCIPAL_INVESTIGATORShun Lu, MD
Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Outcome results
None listed