RAS(ON) Inhibitors for Gastrointestinal Cancer
Recruiting in Palo Alto (17 mi)
+17 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Revolution Medicines, Inc.
Disqualifiers: CNS tumors, Impaired GI function, others
No Placebo Group
Breakthrough Therapy
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.
12345Is 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.
678910What 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.
13111213Eligibility 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.
+2 more
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.
Trial 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
Participant Groups
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.
6Treatment groups
Experimental Treatment
Group I: Subprotocol F: RAS G12D-mutated metastatic PDACExperimental Treatment4 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 PDACExperimental Treatment4 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 PDACExperimental Treatment5 Interventions
RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens
Group IV: Subprotocol C: metastatic PDACExperimental Treatment3 Interventions
RMC-6236 (QD) and Gemcitabine with Nab-paclitaxel
Group V: Subprotocol B: RAS-mutated unresectable or metastatic CRC or metastatic PDACExperimental Treatment3 Interventions
RMC-6236 (QD) and Cetuximab with or without mFOLFOX6
Group VI: Subprotocol A: RAS-mutated unresectable or metastatic CRC or metastatic PDACExperimental Treatment4 Interventions
RMC-6236 (QD) and Bevacizumab with 5-fluorouracil-based regimens
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
NEXT Oncology DallasIrving, TX
Virginia Cancer SpecialistsFairfax, VA
The Sidney Kimmel Comprehensive Cancer Center at John HopkinsBaltimore, MD
Columbia University Medical CenterNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Revolution Medicines, Inc.Lead Sponsor
References
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.
Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas. [2023]Label="Introduction" NlmCategory="UNASSIGNED">In metastatic colorectal cancer (mCRC), RAS mutations impart inferior survival and resistance to anti-epidermal growth factor receptor (EGFR) antibodies. KRAS G12C inhibitors have been developed and we evaluated how KRAS G12C differs from other RAS mutations.
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]Gene mutations in the RAS family rule out metastatic colorectal carcinomas (mCRCs) from anti-EGFR therapies.
Next generation sequencing identifies 'interactome' signatures in relapsed and refractory metastatic colorectal cancer. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making.
Effective MAPK Inhibition is critical for therapeutic responses in colorectal cancer with BRAF mutations. [2020]RAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC) but RAF inhibitor combinations have demonstrated improved efficacy, likely through superior suppression of MAPK signaling. The first identified mechanisms of acquired resistance to these combinations all promote MAPK reactivation, underscoring the MAPK pathway as a critical target in BRAF-mutant CRC.
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.
An update on the current and emerging targeted agents in metastatic colorectal cancer. [2012]Over the past 8 to 10 years, significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). In particular, the development of the targeted biologic agents bevacizumab, cetuximab, and panitumumab, and their integration with cytotoxic chemotherapy regimens has led to improvements in clinical efficacy. Despite these gains, the overall impact of current targeted agents in the treatment of mCRC has been relatively modest, and while 2-year survival has improved, no gains have been made, as of yet, in 5-year survival. Intense efforts continue to be focused on developing novel targeted agents with a different spectrum of activity. Presently, five novel targeted molecules are in phase III trials, including the antiangiogenesis agents aflibercept and ramucirumab, two novel receptor tyrosine kinase inhibitors, regorafenib and brivanib, and the Akt inhibitor perifosine. There are an additional 52 phase II trials investigating a wide range of other candidate molecules. The potential list of approved targeted agents in mCRC seems likely to increase over the next 5 to 10 years. To maximize their potential clinical impact, however, it will be critically important to introduce efficient molecular diagnostic methodologies into the drug development process for the identification and validation of predictive biomarkers for chemosensitivity. This article reviews the development of targeted agents for the treatment of mCRC, including the three molecules currently approved by the US Food and Drug Administration (FDA), as well as the main non-FDA-approved therapeutics currently undergoing phase II and III clinical testing.
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]Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC.
Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer: a case report. [2021]As the knowledge on cancer genetic alterations progresses, it fosters the need for more personalized therapeutic intervention in modern cancer management. Recently, mutations in KRAS, BRAF, and PIK3CA genes have emerged as important mechanisms of resistance to EGFR-targeted therapy in metastatic colorectal cancer (mCRC). Here we report the first case of a mCRC patient whose disease had progressed on standard lines of treatment and for which we devised a personalized therapeutic approach consisting of vemurafenib (Zelboraf) and panitumumab (Vectibix), based on the following molecular profile: BRAF(V600E)-mutant, amplified EGFR (double positive) and WT KRAS, WT PIK3CA, not-amplified HER2 (triple negative). This new combination therapy was well tolerated and resulted in a strong control of the disease. In particular, the vemurafenib-panitumumab combination appears to limit the typical toxicity of single agents, since no cutaneous toxic effects typically associated with vemurafenib were observed. Here we report the first clinical evidence that the combination of an anti-EGFR (panitumumab) and an inhibitor of BRAF(V600E) (vemurafenib) is well tolerated and results in a strong disease control in an extensively pretreated mCRC patient.
Targeting RAS signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. [2018]The V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is frequently dysregulated in colorectal cancer (CRC). It is involved in the modulation of several downstream effectors, that include: Raf/Mek/Erk, PI3K/Akt, RalGDS/p38MAPK, and Rac/Rho, and thereby influences tumorigenesis, the invasive behaviors of tumor cell, and resistance to therapy. There is growing evidence exploring the use of drugs that target these pathways in the treatment of CRC. Cetuximab has been approved for CRC patients without a KRAS mutation, or for EGFR-expressing metastatic CRC, although some of the patients have a mutation of KRAS and NRAS. This review summarizes the recent knowledge about the therapeutic potential of targeting RAS with particular emphasis on recent preclinical and clinical studies in treatment of CRC.
The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study. [2022]KRAS is one of the most frequently mutated oncogenes in colorectal cancer (CRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising activities for corresponding advanced solid tumors, including metastatic CRC (mCRC). However, the prognostic impact of the KRAS G12C mutation remains unclear in patients with mCRC.
Targeting KRAS G12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments. [2022]Identifying mutations in the KRAS gene has become increasingly important in the treatment of colorectal cancer with many prognostic and therapeutic implications. However, efforts to develop drugs that target KRAS mutations have not been successful until more recently with the introduction of the KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). Both agents have demonstrated safety and promising efficacy in preclinical studies and early phase trials, but it appears that not all tumor types harboring the KRAS G12C mutation are sensitive to monotherapy approaches. In particular, patients with colorectal cancer (CRC) derive less benefit compared to those with non-small cell lung cancer (NSCLC), likely due to rapid treatment-induced resistance through increased epidermal growth factor receptor (EGFR) signaling. As a result, combination therapy trials with EGFR inhibitors are currently underway. Here, we will review the available clinical trial data on KRASG12C inhibitors in KRAS G12C-mutated CRC, possible mechanisms of resistance to monotherapy, the research studying why available agents are proving to be less efficacious in CRC compared to NSCLC, and future directions for these promising new drugs.
KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. [2021]Kirsten rat sarcoma viral oncogene (KRAS) G12C mutation occurs in about 4% of colorectal cancers (CRCs). Recently, KRAS G12C was identified to be a potential drug target and predictor of response to the novel on AMG510 target treatment. We described the clinicopathologic features and prognosis of KRAS G12C-mutated metastatic CRCs compared to other KRAS mutation.