RAS(ON) Inhibitors for Gastrointestinal Cancer

Recruiting at 21 trial locations

Overseen By Revolution Medicines

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Revolution Medicines, Inc.

Disqualifiers: CNS tumors, Impaired GI function, others

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

Compensation: Varies

Number of Visits: Unknown

1130 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this platform study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard(s) of Care (SOC) or with novel agents. The current subprotocols include the following: Subprotocol A: RMC-6236 + 5-fluorouracil-based regimens Subprotocol B: RMC-6236 + cetuximab with or without mFOLFOX6 Subprotocol C: RMC-6236 + gemcitabine + nab-paclitaxel Subprotocol D: RMC-9805 with or without RMC-6236 + 5-fluorouracil-based regimens Subprotocol E: RMC-9805 with or without RMC-6236 + cetuximab with or without mFOLFOX6 Subprotocol F: RMC-9805 with or without RMC-6236 + gemcitabine + nab-paclitaxel

Will I have to stop taking my current medications?

The trial information 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 RAS(ON) Inhibitors for treating gastrointestinal cancer?

Recent studies have shown promising results for new drugs targeting the RAS pathway, such as KRASG12C inhibitors, in treating RAS-mutated metastatic colorectal cancer. These drugs, used alone or in combination with other treatments, have demonstrated potential clinical benefits, although resistance remains a challenge. ^{1 2 3 4 5}

Is RMC-6236 safe for use in humans?

Preliminary results from phase I trials indicate that RMC-6236, a pan-RAS inhibitor, is safe and shows promising signs of antitumor activity. ^{6 7 8 9 10}

What makes the drug RMC-6236 unique for treating gastrointestinal cancer?

RMC-6236 is unique because it targets the RAS pathway, which is a common mutation in gastrointestinal cancers, and represents a new approach compared to traditional treatments. Unlike other therapies, it aims to inhibit the active form of RAS proteins, potentially overcoming resistance issues seen with other drugs. ^{1 3 11 12 13}

Research Team

Study Director

Principal Investigator

Revolution Medicines

Eligibility Criteria

This trial is for adults over 18 with specific gastrointestinal cancers, including metastatic pancreatic carcinoma or RAS-mutated colorectal adenocarcinoma. Participants must be in good physical condition (ECOG PS 0-1) and have proper organ function. It's not suitable for those with primary brain tumors or GI issues affecting drug absorption, or who've had major surgery within the last month.

Inclusion Criteria

My pancreatic cancer is aggressive and has spread to other parts.

My organs are functioning well enough for the study.

I am 18 years old or older.

Exclusion Criteria

My cancer originated in the brain or spinal cord.

I have not had major surgery in the last 28 days.

I have a digestive issue that affects how my body absorbs medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Exploration

Part 1 of each subprotocol involves exploring the dose of RMC-6236 and RMC-9805 in combination with other agents

28 days

Dose Expansion

Part 2 of each subprotocol involves expanding the dose to more participants to further evaluate safety and efficacy

21 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• 5-fluorouracil
• Cetuximab
• Gemcitabine
• Nab-paclitaxel
• RMC-6236

Trial Overview The study tests new RAS(ON) inhibitors combined with standard cancer treatments or novel agents in three subprotocols: A) RMC-6236 plus fluorouracil-based regimens; B) RMC-6236 plus cetuximab, optionally with mFOLFOX6; C) RMC-6234 plus gemcitabine and nab-paclitaxel. The goal is to assess safety, tolerability, how the body processes the drugs (PK), and initial effectiveness against tumors.

Participant Groups

Group I: Subprotocol F: RAS G12D-mutated metastatic PDAC Experimental Treatment 4 Interventions

RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Gemcitabine with Nab-paclitaxel

Group II: Subprotocol E: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC Experimental Treatment 4 Interventions

RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Cetuximab with or without mFOLFOX6

Group III: Subprotocol D: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC Experimental Treatment 5 Interventions

RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens

Group IV: Subprotocol C: metastatic PDAC Experimental Treatment 3 Interventions

RMC-6236 (QD) and Gemcitabine with Nab-paclitaxel

Group V: Subprotocol B: RAS-mutated unresectable or metastatic CRC or metastatic PDAC Experimental Treatment 3 Interventions

RMC-6236 (QD) and Cetuximab with or without mFOLFOX6

Group VI: Subprotocol A: RAS-mutated unresectable or metastatic CRC or metastatic PDAC Experimental Treatment 4 Interventions

RMC-6236 (QD) and Bevacizumab with 5-fluorouracil-based regimens

Who Is Running the Clinical Trial?

Revolution Medicines, Inc.

Lead Sponsor

Trials

14

Recruited

4,500+

Findings from Research

New drugs targeting the RAS pathway, such as KRASG12C inhibitors, have shown promising results in clinical trials for treating RAS-mutated metastatic colorectal cancer (mCRC), indicating potential for improved patient outcomes.

Recent insights into adaptive resistance and feedback loops in the RAS pathway have led to the development of strategic combination therapies, which may help overcome resistance issues and enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Developments in Treating RAS-Mutated Metastatic Colorectal Cancer. Janssens, K., Lambrechts, C., Geerinckx, B., et al.[2023]

Patients with metastatic colorectal cancer (mCRC) harboring KRAS G12C mutations have a similar clinical presentation to those with other RAS mutations, but they exhibit distinct copy number alterations in specific genes, which could influence treatment strategies.

While the median overall survival for KRAS G12C (27 months) and other RAS mutations (29 months) is worse compared to wildtype (43 months), the progression-free survival on first chemotherapy for KRAS G12C patients is 11 months, indicating a need for targeted therapies for this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas. Li, M., Keshavarz-Rahaghi, F., Ladua, G., et al.[2023]

In a study of 240 metastatic colorectal carcinoma (mCRC) samples, 52.9% had mutations in the KRAS and NRAS genes, which are critical for determining eligibility for anti-EGFR therapies.

Advanced detection methods revealed that some samples previously classified as wild-type or mutated contained subclonal KRAS mutations, highlighting the importance of using high-sensitivity assays and UDG pre-treatment to avoid misinterpretation of low-frequency mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extreme assay sensitivity in molecular diagnostics further unveils intratumour heterogeneity in metastatic colorectal cancer as well as artifactual low-frequency mutations in the KRAS gene. Mariani, S., Bertero, L., Osella-Abate, S., et al.[2018]

In a study of 32 patients with relapsed and refractory metastatic colorectal cancer (mCRC), a variety of mutations were identified, with TP53 being the most common, indicating a complex mutational landscape that could influence treatment decisions.

The research highlighted that understanding the unique mutational signatures and activated signaling pathways in individual patients can help predict responses to therapies and guide the selection of effective drug combinations, rather than relying solely on dominant oncogene mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation sequencing identifies 'interactome' signatures in relapsed and refractory metastatic colorectal cancer. Johnson, B., Cooke, L., Mahadevan, D.[2022]

RAF inhibitor monotherapy does not work effectively for treating BRAF-mutant colorectal cancer, indicating that single-agent therapies may not be sufficient.

Combining RAF inhibitors with other treatments has shown improved effectiveness by better suppressing MAPK signaling, highlighting the importance of targeting the MAPK pathway in these cancer cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective MAPK Inhibition is critical for therapeutic responses in colorectal cancer with BRAF mutations. Ahronian, LG., Corcoran, RB.[2020]

Phase I trials of RMC-6236, a pan-RAS inhibitor, and HRS-4642, a KRASG12D inhibitor, have shown that both drugs are safe for use and exhibit promising antitumor activity.

These findings highlight the potential of developing RAS-targeted therapies beyond just KRASG12C, indicating a growing interest in more comprehensive treatment options for cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drugging RAS: Moving Beyond KRASG12C. [2023]

Recent advancements in treating metastatic colorectal cancer (mCRC) have included targeted biologic agents like bevacizumab, cetuximab, and panitumumab, which have improved 2-year survival rates but have not yet increased 5-year survival rates.

Currently, five new targeted therapies are in phase III trials, and 52 additional phase II trials are exploring various candidate molecules, highlighting the ongoing efforts to enhance treatment options and the importance of developing molecular diagnostics to identify effective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the current and emerging targeted agents in metastatic colorectal cancer. Chu, E.[2012]

In a phase II trial involving 25 patients with RAS-mutant, microsatellite stable metastatic colorectal cancer, the combination of sintilimab, bevacizumab, oxaliplatin, and capecitabine showed a high objective response rate of 84% and a disease control rate of 100%, indicating promising anti-tumor activity.

The treatment was generally well-tolerated, with manageable adverse events; the most common were anemia and neutropenia, but no grade 5 adverse events occurred, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial. Fang, X., Zhu, N., Zhong, C., et al.[2023]

A personalized treatment approach using the combination of vemurafenib and panitumumab was successfully implemented in a metastatic colorectal cancer patient with a specific genetic profile, leading to strong disease control.

This combination therapy was well tolerated, showing no typical side effects associated with vemurafenib, suggesting it may be a safer option for patients who have progressed on standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer: a case report. Capalbo, C., Marchetti, P., Coppa, A., et al.[2021]

KRAS is often dysregulated in colorectal cancer (CRC) and plays a crucial role in tumor growth and resistance to treatment by affecting various signaling pathways.

Cetuximab is an effective treatment for CRC patients without KRAS mutations, but its efficacy is limited in patients with KRAS or NRAS mutations, highlighting the need for targeted therapies against these mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting RAS signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. Bahrami, A., Hassanian, SM., ShahidSales, S., et al.[2018]

In a study of 1,632 patients with metastatic colorectal cancer (mCRC), those with the KRAS G12C mutation experienced significantly shorter progression-free survival (PFS) and overall survival (OS) compared to those with non-G12C mutations, with median PFS of 9.4 months versus 10.8 months and OS of 21.1 months versus 27.3 months.

The KRAS G12C mutation was independently associated with poorer survival outcomes, highlighting the need for targeted therapies that specifically address this mutation in mCRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study. Chida, K., Kotani, D., Masuishi, T., et al.[2022]

KRASG12C inhibitors, such as sotorasib and adagrasib, show safety and promising efficacy in treating KRASG12C-mutated colorectal cancer (CRC), but their effectiveness is lower compared to non-small cell lung cancer (NSCLC).

Patients with CRC may develop rapid resistance to these therapies due to increased signaling from the epidermal growth factor receptor (EGFR), leading to ongoing trials exploring combination therapies with EGFR inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRAS G12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments. Ji, J., Wang, C., Fakih, M.[2022]

In a study of 839 patients with KRAS-mutated metastatic colorectal cancer (mCRC), 17% had the KRAS G12C mutation, which was linked to a higher likelihood of lung and liver metastases and a lower chance of peritoneal spread.

Patients with the KRAS G12C mutation experienced shorter overall survival compared to those with other KRAS mutations, indicating a need for targeted therapies and tailored treatment approaches for this specific mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. Schirripa, M., Nappo, F., Cremolini, C., et al.[2021]

References

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

New Developments in Treating RAS-Mutated Metastatic Colorectal Cancer. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Extreme assay sensitivity in molecular diagnostics further unveils intratumour heterogeneity in metastatic colorectal cancer as well as artifactual low-frequency mutations in the KRAS gene. [2018]

4. China pubmed.ncbi.nlm.nih.gov

Next generation sequencing identifies 'interactome' signatures in relapsed and refractory metastatic colorectal cancer. [2022]

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

Effective MAPK Inhibition is critical for therapeutic responses in colorectal cancer with BRAF mutations. [2020]

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

Drugging RAS: Moving Beyond KRASG12C. [2023]

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

An update on the current and emerging targeted agents in metastatic colorectal cancer. [2012]

8. England pubmed.ncbi.nlm.nih.gov

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial. [2023]

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

Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer: a case report. [2021]

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

Targeting RAS signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. [2018]

11. England pubmed.ncbi.nlm.nih.gov

The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study. [2022]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Targeting KRAS G12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments. [2022]

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

KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. [2021]