RMC-6291 + RMC-6236 for Advanced Solid Cancers
Recruiting in Palo Alto (17 mi)
+53 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Revolution Medicines, Inc.
Disqualifiers: Primary CNS tumors, Active brain metastases, GI impairment, others
No Placebo Group
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.
12345Eligibility 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.
+7 more
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.
+1 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: RMC-6291 and RMC-6236Experimental Treatment1 Intervention
Dose escalation and Dose expansion
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Stanford Cancer InstituteStanford, CA
Sarah Cannon Research InstitueNashville, TN
MD AndersonHouston, TX
NYU Langone HealthNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Revolution Medicines, Inc.Lead Sponsor
References
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]The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti-vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first-line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed. We investigated the association between the RAS mutation status and clinical outcomes in terms of response rate, progression-free survival (PFS) and overall survival (OS). Mutations in RAS genes were observed in 47 (52.6%) patients (45 KRAS and 2 NRAS mutations). Patients with tumours harbouring RAS mutations were less suitable for primary tumour resection, were more likely to develop lung metastases, and received bevacizumab treatment for a shorter time period compared with those with wild-type tumours. The response rate to chemotherapy did not differ according to the RAS mutation status, and there were no significant differences in PFS [RAS mutation: 12 months, 95% confidence interval (CI): 8.7-15.2 vs. RAS wild-type: 12 months, 95% CI: 9.67-14.32; P=0.857] or OS (RAS mutation: 20 months, 95% CI: 14.3-25.6 vs. RAS wild-type: 24 months, 95% CI: 18.7-29.2; P=0.631). Patients with RAS mutation vs. those with RAS wild-type exhibited a favourable trend in PFS when treated with bevacizumab (13 months, 95% CI: 6.5-19.4 vs. 10 months, 95% CI: 4.2-15.7, respectively; P=0.07) and OS (27 months, 95% CI: 18.5-35.4 vs. 15 months, 95% CI: 12.4-17.5, respectively; P=0.22). In conclusion, RAS mutations are not a prognostic marker for PFS and OS in CRC patients receiving fluoropyrimidine-oxaliplatine treatment, with or without bevacizumab. RAS mutations are not predictive of the lack of efficacy of bevacizumab, and these patients appear to benefit from anti-angiogenic treatment.
Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer. [2023]Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. The RAS pathway is activated in more than 55% of CRC and has been targeted for therapeutic intervention with MEK inhibitors. Unfortunately, many patients have de novo resistance, or can develop resistance to this new class of drugs. We have hypothesized that much of this resistance may pass through SRC as a common signal transduction node, and that inhibition of SRC may suppress MEK inhibition resistance mechanisms. CRC tumors of the Consensus Molecular Subtype (CMS) 4, enriched in stem cells, are difficult to successfully treat and have been suggested to evade traditional chemotherapy agents through resistance mechanisms. Here, we evaluate targeting two pathways simultaneously to produce an effective treatment by overcoming resistance. We show that combining Trametinib (MEKi) with Dasatinib (SRCi) provides enhanced cell death in 8 of the 16 tested CRC cell lines compared to treatment with either agent alone. To be able to select sensitive cells, we simultaneously evaluated a validated 18-gene RAS pathway activation signature score along with a 13-gene MEKi resistance signature score, which we hypothesize predict tumor sensitivity to this dual targeted therapy. We found the cell lines that were sensitive to the dual treatment were predominantly CMS4 and had both a high 18-gene and a high 13-gene score, suggesting these cell lines had potential for de novo MEKi sensitivity but were subject to the rapid development of MEKi resistance. The 13-gene score is highly correlated to a score for SRC activation, suggesting resistance is dependent on SRC. Our data show that gene expression signature scores for RAS pathway activation and for MEKi resistance may be useful in determining which CRC tumors will respond to the novel drug combination of MEKi and SRCi.
New Developments in Treating RAS-Mutated Metastatic Colorectal Cancer. [2023]Label="OPINION STATEMENT">One of the great challenges in digestive oncology is choosing the optimal therapy for RAS-mutated metastatic colorectal cancer (mCRC). Even though the RAS genes and accompanying pathway were identified decades ago and extensive knowledge exists on their role in carcinogenesis, it has proven challenging to translate these insights into new therapies and clinical benefit for patients. However, recently, new drugs targeting this pathway (for example, KRASG12C inhibitors) have shown promising results in clinical trials, as monotherapy or in combination regimens. Although resistance remains an important issue, more knowledge on adaptive resistance and feedback loops in the RAS-pathway has led to strategical combination regimens to overcome this problem. In the past year, many encouraging results have been published or presented at conferences. Even though some of the data is still preliminary, these studies may bring practice-changing results and can lead to a clinical benefit for patients over the coming years. Because of these recent developments, the treatment of RAS-mutated mCRC has become a topic of great interest. Therefore, in this review, we will summarize the standard of care and discuss the most important emerging therapies for this patient population.
Drugging RAS: Moving Beyond KRASG12C. [2023]Preliminary results from phase I trials respectively evaluating RMC-6236, a pan-RAS inhibitor, and HRS-4642, a KRASG12D inhibitor, indicate that both are safe and show promising signs of antitumor activity. These are just two of the candidate RAS therapies in a burgeoning development space as the field looks ahead to drugs that hit more than just KRASG12C.
Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. [2021]Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two oncogenes remain dependent on the activity of a single oncogene. Deinduction of either oncogene individually, or both oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of Kras(G12D) in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and Kras(G12D) transgenes further improved survival. Disease relapse after deinduction of both oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTV-rtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of oncogenes and that targeted approaches will also benefit from combination therapies.