GDC-6036 for KRAS G12C-Mutated Cancers
Recruiting in Palo Alto (17 mi)
+78 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Genentech, Inc.
Disqualifiers: Brain metastases, Malabsorption, Cardiovascular dysfunction, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called GDC-6036 in patients with advanced or metastatic solid tumors that have a KRAS G12C mutation. The drug works by blocking a faulty part of the cancer cells' genetic code to stop their growth.
Do I need to stop my current medications for the trial?
The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug GDC-6036 for KRAS G12C-mutated cancers?
The drug Divarasib (GDC-6036) has shown promising results in treating KRAS G12C-mutated colorectal cancer, especially when combined with cetuximab, with a 62.5% response rate in patients who had not previously received KRAS G12C inhibitors. This suggests that GDC-6036 could be effective in treating cancers with this specific mutation.
12345Is GDC-6036 (Divarasib) safe for humans?
In a study combining Divarasib with another drug, cetuximab, for colorectal cancer, the treatment was generally safe, with some patients needing dose adjustments but no one stopping treatment due to side effects.
12356What makes the drug GDC-6036 unique for KRAS G12C-mutated cancers?
GDC-6036, also known as Divarasib, is a highly potent and selective inhibitor specifically targeting the KRAS G12C mutation, which is a common driver in several cancers. This drug is designed to bind covalently to the mutant protein, offering a novel approach compared to other treatments that may not be as selective or effective for this specific mutation.
13578Eligibility Criteria
This trial is for adults with advanced solid tumors that have a specific mutation called KRAS G12C. Participants must be able to use contraception and not donate eggs or sperm during the study. They can't join if they have serious heart or liver problems, active brain cancer spread, or issues absorbing medicine through their gut.Inclusion Criteria
I am a man who agrees to use contraception or remain abstinent as required.
Women of childbearing potential must agree to remain abstinent or use contraception, and agree to refrain from donating eggs during the treatment period and after the final dose of study treatment as specified in the protocol.
My cancer has a specific KRAS G12C mutation.
Exclusion Criteria
I do not have serious heart or liver problems.
I have cancer that has spread to my brain.
I have a condition that affects how my body absorbs food.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose-Escalation and Dose-Expansion
Participants receive GDC-6036 alone or in combination with other therapies in a dose-escalation and dose-expansion format
Varies by cohort
Multiple visits per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
1 visit (in-person)
Participant Groups
The study is testing the safety and effects of a new drug named GDC-6036, alone or combined with other cancer drugs like Atezolizumab and Cetuximab. It's in early stages (Phase I) to find out how much of the drug can be given safely and how it might help patients.
7Treatment groups
Experimental Treatment
Group I: Arm G: GDC-6036 + Inavolisib (Stage I and Stage II)Experimental Treatment2 Interventions
Participants with solid tumors will receive GDC-6036 in combination with inavolisib PO in Stage I.
Participants with select solid tumors will be treated with GDC-6036 in combination with inavolisib PO in Stage II.
Group II: Arm F: GDC-6036 + GDC-1971 (Stage I and Stage II)Experimental Treatment2 Interventions
Participants with solid tumors will receive GDC-6036 in combination with GDC-1971 PO in Stage I.
Participants with select solid tumors will be treated with GDC-6036 in combination with GDC-1971 PO in Stage II.
Group III: Arm E: GDC-6036 + Erlotinib (Stage I and Stage II)Experimental Treatment2 Interventions
Participants with non-small cell lung cancer will receive GDC-6036 in combination with erlotinib.
Group IV: Arm D: GDC-6036 + Bevacizumab (Stage I and Stage II)Experimental Treatment2 Interventions
Participants with solid tumors will receive GDC-6036 in combination with bevacizumab.
Group V: Arm C: GDC-6036 + Cetuximab (Stage I and Stage II)Experimental Treatment2 Interventions
Participants with colorectal cancer will receive GDC-6036 in combination with cetuximab.
Group VI: Arm B: GDC-6036 + Atezolizumab (Stage I and Stage II)Experimental Treatment2 Interventions
Participants with non-small cell lung cancer will receive GDC-6036 in combination with atezolizumab.
Group VII: Arm A: Dose-escalation (Stage I), Dose Expansion (Stage II)Experimental Treatment1 Intervention
Participants in Stage I will receive GDC-6036 administered orally once daily (PO QD). The dose will be increased in successive cohorts until a study-specific threshold is reached.
Participants with select solid tumors will be treated with GDC-6036 PO QD in Stage II.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UCSD Moores Cancer CenterLa Jolla, CA
University of OklahomaOklahoma City, OK
Abramson Cancer CenterPhiladelphia, PA
Jewish General HospitalMontreal, Canada
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Genentech, Inc.Lead Sponsor
References
Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. [2023]Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity.
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. [2023]KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.
Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. [2023]Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.
Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer. [2022]The KRAS p.G12C mutation has recently become an actionable drug target. To further understand KRAS p.G12C disease, we describe clinicopathologic characteristics, treatment patterns, overall survival (OS), and real-world progression-free survival (rwPFS) in patients with metastatic colorectal cancer (mCRC), KRAS p.G12C mutations (KRAS G12C), and other KRAS mutations (KRAS non-G12C) using a de-identified database.
Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. [2023]KRAS G12C mutations are critical in the pathogenesis of multiple cancer types, including non-small cell lung (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal (CRC) cancers. As such, they have increasingly become a target of novel therapies in the management of these malignancies. However, the therapeutic success of KRAS G12C inhibitors to date has been far more limited in CRC and PDAC than NSCLC. In this review, we briefly summarize the biochemistry of KRAS targeting and treatment resistance, highlight differences in the epidemiology of various G12C-mutated cancers, and provide an overview of the published data on KRAS G12C inhibitors for various indications. We conclude with a summary of ongoing clinical trials in G12C-mutant CRC and a discussion of future directions in the management of this disease. KRAS G12C mutation, targeted therapies, colorectal cancer, non-small cell lung cancer, pancreatic cancer, drug development.
Mechanisms of Resistance to KRASG12C Inhibitors. [2021]KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of "undruggable". Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.
Clinicopathologic Characteristics and Outcomes for Patients With KRAS G12D-Mutant NSCLC. [2022]Label="Introduction" NlmCategory="UNASSIGNED">Co-occurring mutations in KRAS-mutant NSCLC are associated with discrete biological properties and modulate therapeutic susceptibilities. As G12D-specific inhibitors are expected to enter the clinic, we sought to investigate the characteristics and outcomes of patients with KRAS G12D-mutant NSCLC.
KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing. [2021]Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non-small cell lung cancer, occurring in approximately 30% of lung adenocarcinomas. Over 80% of oncogenic KRAS mutations occur at codon 12, where the glycine residue is substituted by different amino acids, leading to genomic heterogeneity of KRas-mutant tumors. The KRAS glycine-to-cysteine mutation (G12C) composes approximately 44% of KRAS mutations in non-small cell lung cancer, with mutant KRasG12C present in approximately 13% of all patients with lung adenocarcinoma. Mutant KRas has been an oncogenic target for decades, but no viable therapeutic agents were developed until recently. However, advances in KRas molecular modeling have led to the development and clinical testing of agents that directly inhibit mutant KRasG12C. These agents include sotorasib (AMG-510), adagrasib (MRTX-849), and JNJ-74699157. In addition to testing for known actionable oncogenic driver alterations in EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, and NTRK and for the expression of programmed cell-death protein ligand 1, pathologists, medical oncologists, and community practitioners will need to incorporate routine testing for emerging biomarkers such as MET amplification, ERBB2 (alias HER2), and KRAS mutations, particularly KRAS G12C, considering the promising development of direct inhibitors of KRasG12C protein.