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. ^{1 2 3 4 5}

Is 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. ^{1 2 3 5 6}

What 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. ^{1 3 5 7 8}

Research Team

Clinical Trials

Principal Investigator

Genentech, Inc.

Eligibility 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)

Treatment Details

Interventions

• GDC-6036 (KRAS G12C Inhibitor)

Trial Overview 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.

Participant Groups

Group I: Arm G: GDC-6036 + Inavolisib (Stage I and Stage II) Experimental Treatment 2 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 Treatment 2 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 Treatment 2 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 Treatment 2 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 Treatment 2 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 Treatment 2 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 Treatment 1 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.

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that showed promising efficacy in patients with advanced solid tumors, achieving a confirmed response rate of 53.4% in non-small-cell lung cancer (NSCLC) and 29.1% in colorectal cancer, with median progression-free survival of 13.1 months and 5.6 months, respectively.

The treatment was generally well-tolerated, with no dose-limiting toxic effects or treatment-related deaths reported, although 93% of patients experienced treatment-related adverse events, mostly low-grade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. Sacher, A., LoRusso, P., Patel, MR., et al.[2023]

The combination of divarasib and cetuximab in treating KRAS G12C-positive colorectal cancer showed a manageable safety profile, with only 13.8% of patients experiencing treatment-related adverse events that required dose reductions, and no treatment withdrawals.

This combination therapy demonstrated promising antitumor activity, achieving a 62.5% objective response rate in previously untreated patients, with a median progression-free survival of 8.1 months, indicating its potential effectiveness in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Desai, J., Alonso, G., Kim, SH., et al.[2023]

In a clinical trial involving 44 patients with metastatic colorectal cancer and mutant KRAS G12C, adagrasib showed a 19% response rate as a monotherapy, with a median response duration of 4.3 months.

When combined with cetuximab, the response rate increased to 46%, with a median response duration of 7.6 months, indicating that the combination therapy may be more effective than monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. Yaeger, R., Weiss, J., Pelster, MS., et al.[2023]

In a study of 6477 patients with metastatic colorectal cancer (mCRC), only 3.7% had the KRAS p.G12C mutation, which is associated with poorer treatment outcomes compared to patients with other KRAS mutations, indicating a significant unmet medical need for effective therapies targeting this mutation.

Patients with KRAS p.G12C mutations had a median overall survival of 16.1 months and a real-world progression-free survival of 7.4 months, both of which were lower than those for patients with other KRAS mutations, suggesting that KRAS p.G12C may have negative prognostic implications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer. Fakih, M., Tu, H., Hsu, H., et al.[2022]

KRAS G12C mutations are important in several cancers, particularly non-small cell lung cancer (NSCLC), where targeted therapies have shown more success compared to colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC).

The review discusses the biochemical mechanisms of KRAS targeting, treatment resistance, and ongoing clinical trials for KRAS G12C inhibitors in CRC, indicating a need for further research to improve therapeutic outcomes in this cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. Qunaj, L., May, MS., Neugut, AI., et al.[2023]

In a study of 107 patients with KRAS G12D-mutant non-small cell lung cancer (NSCLC), co-occurring mutations in STK11 and KEAP1 were linked to significantly worse progression-free and overall survival outcomes, indicating their potential role in therapeutic resistance.

Among patients treated with first-line therapy, those with STK11 co-mutations had a median progression-free survival of only 1.2 months compared to 4.1 months for those without, highlighting the impact of these mutations on treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinicopathologic Characteristics and Outcomes for Patients With KRAS G12D-Mutant NSCLC. Cooper, AJ., Muzikansky, A., Lennerz, J., et al.[2022]

KRAS mutations, particularly the G12C variant, are prevalent in non-small cell lung cancer, occurring in about 30% of lung adenocarcinomas, with G12C mutations found in approximately 13% of all patients with this type of cancer.

Recent advancements have led to the development of targeted therapies, such as sotorasib and adagrasib, that directly inhibit the KRasG12C mutation, highlighting the importance of routine testing for KRAS mutations in lung cancer patients to guide treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing. Veluswamy, R., Mack, PC., Houldsworth, J., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Mechanisms of Resistance to KRASG12C Inhibitors. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Clinicopathologic Characteristics and Outcomes for Patients With KRAS G12D-Mutant NSCLC. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing. [2021]