RMC-6236 for Pancreatic Cancer

(RASolute 302 Trial)

Recruiting at 65 trial locations

Overseen By Revolution Medicines

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Revolution Medicines, Inc.

Must not be taking: RAS-targeted therapy

Disqualifiers: CNS metastases, Major surgery, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 3 years

460 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, RMC-6236 (a RAS(ON) inhibitor), for treating pancreatic cancer. Researchers aim to assess the safety and effectiveness of this treatment compared to standard chemotherapy options. The trial seeks participants with metastatic pancreatic cancer and a specific gene change known as a RAS mutation. Participants must be able to take oral medication and have good organ function. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that RMC-6236 is likely to be safe for humans?

Research has shown that RMC-6236 appears safe for patients. In earlier studies, this treatment was tested at various doses and was generally well-tolerated. No serious or unexpected side effects were reported, which is encouraging. Researchers are also examining progression-free survival, the duration patients live without their cancer worsening. This measure helps assess both the safety and effectiveness of the treatment. Although studies are ongoing, results so far are positive, suggesting that RMC-6236 could be a safe option for people with pancreatic cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about RMC-6236 because, unlike traditional chemotherapy options like Gemcitabine and nab-paclitaxel or FOLFIRINOX, this treatment is designed to target specific molecular pathways in pancreatic cancer cells. While standard treatments generally attack all rapidly dividing cells, RMC-6236 aims to hone in on the cancerous cells, potentially offering a more precise approach. This targeted action could lead to fewer side effects and improved effectiveness, bringing new hope for better outcomes in pancreatic cancer treatment.

What evidence suggests that RMC-6236 might be an effective treatment for pancreatic cancer?

Research has shown that RMC-6236, one of the treatments studied in this trial, may help treat pancreatic cancer. Studies have found that it can shrink or slow tumor growth over time. Some evidence suggests that patients lived longer without their cancer worsening and had an overall longer life when using RMC-6236. Additionally, early tests showed a decrease in cancer-related DNA in the blood, indicating the drug's effectiveness. These findings suggest that RMC-6236 could be an effective treatment option for pancreatic cancer. Participants in this trial may receive RMC-6236 or be assigned to the investigator's choice of standard care therapy. ^{1 2 3 4 6}

Who Is on the Research Team?

Study Director

Principal Investigator

Revolution Medicines

Are You a Good Fit for This Trial?

This trial is for patients with advanced pancreatic cancer (PDAC) who have already undergone treatment. Participants should be adults with a confirmed diagnosis and measurable disease, able to perform daily activities with relative independence.

Inclusion Criteria

Measurable disease per RECIST 1.1

My pancreatic cancer has spread and was confirmed by lab tests.

I am fully active or can carry out light work.

Exclusion Criteria

I have no conditions that affect my ability to take or absorb medications.

I have been treated with drugs targeting RAS proteins.

I cannot or do not want to follow the study's required visits or procedures.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either RMC-6236 or Investigator's choice of standard of care chemotherapy

Up to approximately 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 3 years

What Are the Treatments Tested in This Trial?

Interventions

• RMC-6236

Trial Overview The study tests RMC-6236, a new potential drug targeting specific cancer pathways, against standard chemotherapy treatments like 5-fluorouracil, irinotecan, nab-paclitaxel, gemcitabine, oxaliplatin and liposomal irinotecan combined with leucovorin.

How Is the Trial Designed?

Group I: RMC-6236 Experimental Treatment 1 Intervention

Study drug

Group II: Investigator's choice of standard of care therapy Active Control 7 Interventions

Patients randomized to Investigator's choice of standard of care chemotherapy will receive one of the following four treatments: * Gemcitabine and nab-paclitaxel (GnP) * Oxaliplatin, leucovorin, irinotecan, and 5-FU (Modified FOLFIRINOX: mFOLFIRINOX) * Liposomal irinotecan (Nal-IRI + 5-FU/LV) * Oxaliplatin, leucovorin and 5-FU IV (FOLFOX)

Who Is Running the Clinical Trial?

Revolution Medicines, Inc.

Lead Sponsor

Trials

14

Recruited

4,500+

Published Research Related to This Trial

In a phase 2 clinical trial involving 137 patients with metastatic pancreatic cancer, the combination of selumetinib and MK-2206 did not improve overall survival compared to the standard mFOLFOX treatment, with median survival times of 3.9 months versus 6.7 months, respectively.

The experimental treatment resulted in more severe side effects, with 39 patients experiencing grade 3 or higher toxic effects compared to 23 in the mFOLFOX group, leading to a higher rate of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. Chung, V., McDonough, S., Philip, PA., et al.[2022]

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]

The small-molecule KRASG12D inhibitor, MRTX1133, demonstrated significant efficacy in treating pancreatic ductal adenocarcinoma (PDAC) in various models, leading to deep tumor regressions and complete remissions within 14 days.

MRTX1133's effectiveness relies on the immune system, particularly T cells, indicating that it not only targets cancer cells directly but also alters the tumor microenvironment, making it a promising candidate for clinical trials and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer. Kemp, SB., Cheng, N., Markosyan, N., et al.[2023]

K-RAS is essential for the maintenance of pancreatic tumors with K-RAS mutations, as demonstrated by the impaired tumor growth in xenograft models when K-RAS was knocked down.

Inhibition of the MAPK pathway (specifically MEK) led to tumor regression in pancreatic xenografts, suggesting that combining MEK inhibitors with PI3K inhibitors could enhance treatment efficacy for patients with K-RAS mutant pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo. Hofmann, I., Weiss, A., Elain, G., et al.[2022]

MRTX1133, a drug targeting the KRASG12D mutation in pancreatic ductal adenocarcinoma (PDAC), has shown effectiveness at low concentrations in patient-derived organoid models and cell lines, indicating its potential as a treatment option.

Combining MRTX1133 with the pan-ERBB inhibitor afatinib not only enhanced antitumor activity but also overcame resistance in cancer cells, leading to tumor regression and improved survival in mouse models, suggesting a promising strategy for treating KRAS mutant pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma. Gulay, KCM., Zhang, X., Pantazopoulou, V., et al.[2023]

KRAS mutations play a crucial role in pancreatic ductal adenocarcinoma (PDAC), and the study found that KRAS inhibitors BI-3406 and sotorasib, alone or in combination with other inhibitors, showed cytotoxic effects on specific PDAC cell lines.

The combination of BI-3406 with trametinib and buparlisib enhanced anti-tumor efficacy in certain cell lines, indicating that targeting KRAS and its downstream pathways could be a promising therapeutic strategy for PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of KRAS, MEK and PI3K Demonstrate Synergistic Anti-Tumor Effects in Pancreatic Ductal Adenocarcinoma Cell Lines. Ma, Y., Schulz, B., Trakooljul, N., et al.[2022]

Current treatments for pancreatic cancer are inadequate, highlighting the need for new approaches.

Recent research into the genetic mechanisms of pancreatic cancer has led to the development of targeted molecular medicines that focus on specific signaling pathways, such as RAS-MAPK, PI3K-AKT-mTOR, and hedgehog pathways, which may offer new therapeutic options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular targeting therapy for pancreatic cancer: current knowledge and perspectives from bench to bedside. Furukawa, T.[2021]

The combination of the plant-derived compound AMR-MeOAc and the antiapoptotic protein inhibitor FL118 shows synergistic cytotoxic effects against pancreatic cancer cells, regardless of KRAS mutation status, suggesting a promising new treatment strategy.

In cells with the KRASG12D mutation, this combination treatment inhibits mutant KRAS activity, increases reactive oxygen species (ROS) levels, induces apoptosis, and reduces the expression of survival proteins, indicating a multifaceted mechanism of action that could help overcome resistance in pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple mechanisms involved in a low concentration of FL118 enhancement of AMR-MeOAc to induce pancreatic cancer cell apoptosis and growth inhibition. Rabi, T., Li, F.[2020]

KRAS mutations are present in 90% of pancreatic ductal adenocarcinoma (PDAC) cases, driving critical processes like cell growth and drug resistance, making it a key target for treatment.

Targeted therapies aimed at RAS signaling pathways (like MEK, ERK, PI3K, and mTOR) have shown promise in preclinical studies, but the complexity of RAS signaling necessitates exploring combination therapies to effectively combat therapeutic resistance in PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS-related proteins in pancreatic cancer. Mann, KM., Ying, H., Juan, J., et al.[2022]

In a phase II study involving 160 patients with untreated metastatic pancreatic adenocarcinoma, the combination of trametinib and gemcitabine did not significantly improve overall survival (OS) compared to gemcitabine alone, with median OS of 8.4 months versus 6.7 months.

The study also found that while trametinib was associated with more frequent side effects like thrombocytopenia and diarrhea, it did not enhance progression-free survival (PFS), overall response rate (ORR), or duration of response (DOR) in patients, regardless of their KRAS mutation status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Infante, JR., Somer, BG., Park, JO., et al.[2022]

Citations

1. ir.revmed.com ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-updated-data-rmc-6236-monotherapy

Revolution Medicines Presents Updated Data from RMC ... RMC-6236 demonstrated durable antitumor activity as evidenced by updated progression-free survival (PFS) and overall survival (OS) at daily doses ranging from ...

2. ir.revmed.com ir.revmed.com/news-releases/news-release-details/revolution-medicines-rason-multi-selective-inhibitor

Revolution Medicines' RAS(ON) Multi-Selective Inhibitor ... Revolution Medicines' RAS(ON) Multi-Selective Inhibitor Daraxonrasib Granted U.S. FDA Orphan Drug Designation in Pancreatic Cancer. October ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05379985

NCT05379985 | Study of RMC-6236 in Patients With ... This is a Phase 1/1b, multicenter open-label study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of escalating doses of ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.722

Safety, efficacy, and on-treatment circulating tumor DNA ... We report safety, updated efficacy, and exploratory analyses of early ctDNA reduction with clinically active doses of RMC-6236 in patients with RAS mutant PDAC.

5. ir.revmed.com ir.revmed.com/news-releases/news-release-details/revolution-medicines-shares-new-clinical-results-supporting

Revolution Medicines Shares New Clinical Results ... Efficacy: Daraxonrasib at 300 mg QD demonstrated compelling antitumor activity and durability, with the following results for patients with ...

6. breakthroughcancer.org breakthroughcancer.org/2024/12/rason-inhibitor-biomarker-trial-pancreatic-cancer/

Break Through Cancer and Revolution Medicines ... The expanded phase 1 clinical trial is using serial biopsies and blood samples to analyze the tumor response to RMC-6236 at an unprecedented ...