RMC-6291 + RMC-6236 for Advanced Solid Cancers

Recruiting at 54 trial locations

Overseen By Revolution Medicines, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Revolution Medicines, Inc.

Disqualifiers: Primary CNS tumors, Active brain metastases, GI impairment, others

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

Compensation: Varies

Number of Visits: Unknown

210 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is to evaluate the safety, tolerability, and PK profiles of RMC-6291 and RMC-6236 in adults with KRAS G12C-mutated solid tumors.

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 RMC-6291 + RMC-6236 for advanced solid cancers?

Preliminary results from phase I trials indicate that RMC-6236, a pan-RAS inhibitor, is safe and shows promising signs of antitumor activity, suggesting potential effectiveness in treating cancers with RAS mutations. ^{1 2 3 4 5}

Research Team

Revolution Medicines, Inc.

Principal Investigator

Revolution Medicines, Inc.

Eligibility Criteria

This trial is for adults with advanced solid tumors that have a specific mutation (KRAS G12C). Participants must have tried other treatments like immunotherapy and chemotherapy. They should be in good physical condition, but can't join if they've had recent surgery or active brain metastases.

Inclusion Criteria

I have NSCLC and was treated with immunotherapy, chemotherapy, and KRAS G12C inhibitors.

I have solid tumors that were treated before.

My cancer is advanced, cannot be cured with surgery, and has a specific KRAS mutation.

Exclusion Criteria

My cancer originated in the brain or spinal cord.

I haven't had major surgery in the last 28 days or minor surgery in the last 7 days.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of RMC-6291 and RMC-6236 to identify the maximum tolerated dose

21 weeks

Dose Expansion

Participants receive the recommended Phase 2 dose to assess preliminary antitumor activity

21 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• RMC-6236
• RMC-6291

Trial Overview The study tests the combination of two drugs, RMC-6291 and RMC-6236, on patients with KRAS G12C-mutated tumors to assess safety, how well the body tolerates them, and how the body processes these drugs.

Participant Groups

Group I: RMC-6291 and RMC-6236 Experimental Treatment 1 Intervention

Dose escalation and Dose expansion

Who Is Running the Clinical Trial?

Revolution Medicines, Inc.

Lead Sponsor

Trials

14

Recruited

4,500+

Findings from Research

In a study of 93 colorectal cancer patients, RAS mutations were found in over half of the participants, but these mutations did not negatively impact the effectiveness of chemotherapy or the anti-VEGF drug bevacizumab, as there were no significant differences in progression-free survival (PFS) or overall survival (OS) between patients with RAS mutations and those without.

Interestingly, patients with RAS mutations showed a trend towards better PFS and OS when treated with bevacizumab, suggesting that RAS mutations do not predict a lack of benefit from anti-angiogenic therapy, and may even indicate a favorable response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis. Garde Noguera, J., Jantus-Lewintre, E., Gil-Raga, M., et al.[2020]

Combining Trametinib (a MEK inhibitor) with Dasatinib (an SRC inhibitor) enhances cell death in colorectal cancer (CRC) cell lines, particularly in those classified as Consensus Molecular Subtype 4 (CMS4), which are known for their resistance to traditional therapies.

The study suggests that gene expression signature scores related to RAS pathway activation and MEK inhibitor resistance can help predict which CRC tumors are likely to respond to this dual-targeted therapy, potentially improving treatment outcomes for patients with resistant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer. Davis, TB., Gupta, S., Yang, M., et al.[2023]

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]

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]

In a study using mouse models, tumors driven by the cooperation of two oncogenes (Myc and mutant Kras) were found to depend on the activity of just one of these oncogenes for their survival, indicating a potential target for therapy.

Deinducing either oncogene led to tumor regression, and simultaneous deinduction of both resulted in improved survival, suggesting that combination therapies targeting multiple oncogenes could enhance treatment efficacy and prevent relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. Podsypanina, K., Politi, K., Beverly, LJ., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer. [2023]

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

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

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

Drugging RAS: Moving Beyond KRASG12C. [2023]

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

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. [2021]