GDC-6036 for KRAS G12C-Mutated Cancers

Not currently recruiting at 103 trial locations

Overseen By Reference Study ID Number: GO42144 whttps://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Genentech, Inc.

Disqualifiers: Brain metastases, Malabsorption, Cardiovascular dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug called GDC-6036 (also known as Divarasib) for individuals with advanced cancers that have a specific mutation called KRAS G12C. The goal is to assess its safety, how the body processes it, and its effectiveness against these challenging cancers. The study evaluates GDC-6036 alone and in combination with other treatments, such as erlotinib for lung cancer or cetuximab for colorectal cancer. Suitable candidates have an advanced solid tumor with the KRAS G12C mutation. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that GDC-6036, also known as divarasib, is generally safe when used alone or with other treatments. Studies have mostly found mild side effects for GDC-6036 by itself. Patients using GDC-6036 with cetuximab also reported it to be generally safe, and this combination showed promise in fighting tumors with a specific mutation.

While direct information on GDC-6036 used with other drugs like erlotinib, bevacizumab, atezolizumab, or inavolisib is lacking, GDC-6036 is designed to effectively target cancer cells, reducing harm to normal cells. As this study is in its early stages, it aims to confirm safety and determine the right dose. Although initial results are promising, more research is needed to fully understand its safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about GDC-6036 for KRAS G12C-mutated cancers because it targets a specific genetic mutation known as KRAS G12C, which is involved in various solid tumors, including non-small cell lung cancer and colorectal cancer. Unlike traditional treatments such as chemotherapy that attack both healthy and cancerous cells, GDC-6036 works by directly inhibiting the KRAS G12C mutation, potentially leading to more precise and effective results with fewer side effects. The combination of GDC-6036 with other drugs like erlotinib, bevacizumab, and cetuximab aims to enhance its effectiveness and tackle the cancer from multiple angles, offering new hope for patients whose tumors harbor this specific mutation.

What evidence suggests that this trial's treatments could be effective for KRAS G12C-mutated cancers?

Research has shown that GDC-6036, also known as divarasib, yields promising results for treating cancers with the KRAS G12C mutation. Studies have found that patients with this mutation respond well to the drug, which is generally well-tolerated. Specifically, divarasib effectively slowed tumor growth in early tests. In this trial, one group of participants will receive GDC-6036 combined with cetuximab, which achieved a 62.5% response rate in patients with colorectal cancer in previous studies. These findings suggest that GDC-6036 could be a good option for treating cancers with the KRAS G12C mutation. ^{1 2 3 4 6}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Genentech, Inc.

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• GDC-6036

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 is a challenging oncogene to target, but recent subtype-specific inhibitors like adagrasib and sotorasib have shown promising early efficacy in clinical trials for patients with KRASG12C mutations.

Despite their potential, resistance to G12C inhibitors is a concern, and the review discusses strategies for combination therapies to enhance effectiveness, targeting pathways such as SHP2 and PD1/PDL1 to overcome this resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of Resistance to KRASG12C Inhibitors. Dunnett-Kane, V., Nicola, P., Blackhall, F., et al.[2021]

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 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]

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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2303810

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a ... The KRAS G12C mutation is present in approximately 12 to 14% of patients with non–small-cell lung cancer (NSCLC), 4% of patients with colorectal ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04449874

NCT04449874 | A Study to Evaluate the Safety, ... This is a Phase I dose-escalation and dose-expansion study that will evaluate the safety, pharmacokinetics (PK), and preliminary activity of GDC-6036

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00040

Single-Agent Divarasib in Patients With <i>KRAS G12C</i> Divarasib (GDC-6036), an oral, highly potent and selective next-generation KRAS G12C inhibitor, has demonstrated a manageable safety profile and promising ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11111488/

Divarasib in the Evolving Landscape of KRAS G12C Inhibitors ... A multicenter retrospective chart review of clinical outcomes among patients with KRAS G12C mutant non-small cell lung cancer. Clin Lung Cancer.

5. humanforschung-schweiz.ch humanforschung-schweiz.ch/en/trial-search/study-detail/52495/translate/en/?cHash=1b4d44ecf69e37ab9f607ebdf08921be

A study to assess the safety, pharmacokinetics, and ... When mice with tumors with the KRAS G12C mutation received GDC-6036, it slowed or stopped the growth of the cancer cells. This will be the first time GDC-6036 ...

6. dialogorochecac.com dialogorochecac.com/content/dam/roche-dialogo/global-assets/downloadable-assets/congresos-y-eventos/oncology/roche-wclc-2022/presentation/wclc-2022-presentation-adrian-phase-Ia-study-to-evaluate-gdc-6036--monotherapy.pdf

Phase Ia study to evaluate GDC-6036 monotherapy in ... AACR 2022. Page 4. Phase I study evaluates single agent GDC-6036 in advanced or metastatic solid tumors with KRAS G12C mutation. GO42144, NCT04449874 - Data ...