RMC-6236 for Cancer

Recruiting at 15 trial locations

Overseen By Revolution Medicines, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Revolution Medicines, Inc.

Disqualifiers: CNS tumors, 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

Duration: up to 2.5 years

614 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called RMC-6236, which is taken by mouth and targets a protein called RAS. It is aimed at adults with advanced cancers that have specific mutations in the RAS protein. The drug works by blocking this protein, which helps stop the cancer cells from growing.

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 team or your doctor.

Is RMC-6236 safe for humans?

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

What makes the drug RMC-6236 unique for cancer treatment?

RMC-6236 is unique because it is a pan-RAS inhibitor, meaning it targets multiple RAS mutations, not just a single one like KRASG12C inhibitors. This broader approach may offer a more comprehensive treatment option for cancers driven by various RAS mutations. ^{2 6 7 8 9}

What data supports the effectiveness of the drug RMC-6236 for cancer?

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. ^{2 7 10 11 12}

Research Team

Revolution Medicines, Inc.

Principal Investigator

Revolution Medicines, Inc.

Eligibility Criteria

This trial is for adults with advanced solid tumors that have specific RAS mutations, who've already tried standard treatments. They need to be relatively healthy and active (ECOG status of 0 or 1), with good organ function. It's not for those with primary brain tumors, untreated brain metastases, issues absorbing oral meds, or other serious health problems.

Inclusion Criteria

My organs are working well.

I have received the standard treatment for my cancer type and stage.

My advanced cancer has specific KRAS G12 or RAS mutations.

Exclusion Criteria

I do not have any serious health issues that could affect my safety or participation in the study.

I have issues with my digestive system that might affect my ability to take pills.

My cancer originated in the brain or spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive escalating doses of RMC-6236 to evaluate safety, tolerability, and pharmacokinetics

up to 2.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• RMC-6236

Trial Overview The study tests the safety and how well people tolerate RMC-6236, a new medication aimed at treating various types of cancer like lung and colorectal cancer that have certain genetic changes known as RAS mutations.

Participant Groups

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

Enrollment into dose exploration may be from any advanced solid tumor type with KRAS p.G12 mutations. Enrollment into dose expansion/optimization may be from groups consisting of patients with a single histotype/genotype (for example, KRAS G12-mutated NSCLC, PDAC, CRC, RAS mutant NSCLC, Melanoma, gynecological cancer or other solid tumors not previously specified). RAS mutant is defined as any nonsynonymous mutation of KRAS, NRAS, or HRAS at codons 12, 13, or 61 (G12, G13, or Q61)

Who Is Running the Clinical Trial?

Revolution Medicines, Inc.

Lead Sponsor

Trials

14

Recruited

4,500+

Findings from Research

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]

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]

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]

In a study of 120 patients with metastatic colorectal cancer, those with KRAS G12C mutations had a significantly lower response rate to standard chemotherapy plus Bevacizumab compared to patients with other KRAS mutations (27% vs 52% partial response).

Despite the lower response rates in KRAS G12C mutated patients, there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the two groups, suggesting that new treatment strategies targeting KRAS G12C should be explored in combination with standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab. Giampieri, R., Lupi, A., Ziranu, P., et al.[2022]

In metastatic colorectal cancer (mCRC), the choice of second-line treatment after disease progression is crucial and should be guided by specific molecular characteristics, such as RAS and BRAF mutations, which influence eligibility for therapies like anti-EGFR agents.

Continuing bevacizumab treatment beyond progression or switching to other anti-angiogenic agents can improve survival, while RAS wild-type patients may benefit from anti-EGFR monoclonal therapies, highlighting the importance of personalized treatment strategies based on molecular biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era. Giordano, G., Parcesepe, P., Bruno, G., et al.[2021]

In a phase I trial involving 24 patients with advanced cancers, salirasib was generally well tolerated, with the most common side effect being mild to moderate diarrhea in 79% of participants, but no severe toxicities were observed.

The study found that 29% of patients experienced stable disease for at least 4 months, suggesting potential efficacy, and the recommended dose for future studies is 600 mg taken twice daily.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 first-in-human clinical study of S-trans,trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors. Tsimberidou, AM., Rudek, MA., Hong, D., et al.[2012]

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]

Recent advancements have led to the development of effective inhibitors targeting the KRASG12C mutation, highlighting the potential for pharmacological intervention in RAS-driven tumors.

There is an ongoing need to create therapies for other mutant RAS proteins, and new anti-RAS biologics are emerging that could reveal novel vulnerabilities for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the "undruggable" RAS with biologics. Whaby, M., Khan, I., O'Bryan, JP.[2023]

A combination therapy using Torin 1, MK2206, and selumetinib showed significant effectiveness in destroying colorectal cancer cells in 3D cultures, indicating that the treatment is more effective in a more realistic tumor environment than in traditional 2D cultures.

The treatment's success was linked to the presence of specific mutations in the PI3K and RAS-RAF-MAPK pathways, suggesting that this therapy could be tailored to target CRC patients based on their genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective Eradication of Colon Cancer Cells Harboring PI3K and/or MAPK Pathway Mutations in 3D Culture by Combined PI3K/AKT/mTOR Pathway and MEK Inhibition. Atanasova, VS., Riedl, A., Strobl, M., et al.[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]

In a study of 43 lung cancer patients treated with the KRAS(G12C) inhibitor sotorasib, multiple genetic alterations were identified as potential causes of resistance, including mutations in KRAS, NRAS, and BRAF.

Targeting ERK signaling pathways alongside KRAS(G12C) inhibitors may enhance treatment effectiveness and delay resistance, suggesting a need for further clinical trials to explore this combination strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diverse alterations associated with resistance to KRAS(G12C) inhibition. Zhao, Y., Murciano-Goroff, YR., Xue, JY., et al.[2022]

Combining multi-tyrosine kinase PKC inhibitors with MEK1/2 or KRASG12C inhibitors shows promise in treating KRAS-mutated lung cancers, demonstrating cytotoxic effects in both laboratory and animal models.

The study identifies MYC overexpression as a potential resistance mechanism to these therapies, suggesting that targeting MYC could enhance the effectiveness of MEK1/2 and KRASG12C inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer. Macaya, I., Roman, M., Welch, C., et al.[2023]

References

1. 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]

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

Drugging RAS: Moving Beyond KRASG12C. [2023]

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

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab. [2022]

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

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Phase 1 first-in-human clinical study of S-trans,trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors. [2012]

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

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

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

Targeting the "undruggable" RAS with biologics. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Selective Eradication of Colon Cancer Cells Harboring PI3K and/or MAPK Pathway Mutations in 3D Culture by Combined PI3K/AKT/mTOR Pathway and MEK Inhibition. [2023]

10. 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]

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

Diverse alterations associated with resistance to KRAS(G12C) inhibition. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer. [2023]