RAS Inhibitors + Standard Treatments for Lung Cancer
Recruiting in Palo Alto (17 mi)
+58 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 each other.
The first three subprotocols include the following:
Subprotocol A: RMC-6291 +/- RMC-6236 + SOC Subprotocol B: RMC-6236 + SOC Subprotocol C: RMC-9805 +/- RMC-6236 + SOC
Do I have to stop taking my current medications for the trial?
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 drugs used in the RAS Inhibitors + Standard Treatments for Lung Cancer trial?
Research shows that pemetrexed combined with cisplatin or carboplatin is effective in treating advanced non-small cell lung cancer (NSCLC), with studies indicating good survival rates and tolerability. Additionally, pemetrexed is a key chemotherapy drug for malignant pleural mesothelioma, further supporting its use in cancer treatment.
12345Is the combination of RAS inhibitors and standard treatments for lung cancer safe for humans?
The combination of pemetrexed, cisplatin/carboplatin, and pembrolizumab has been studied for safety in lung cancer patients. These treatments have shown acceptable safety profiles, with some patients experiencing side effects like anemia (low red blood cell count), neutropenia (low white blood cell count), and renal (kidney) issues, but these were generally manageable.
15678What makes the RAS Inhibitors + Standard Treatments for Lung Cancer unique?
This treatment is unique because it combines standard chemotherapy drugs like carboplatin and cisplatin with RAS inhibitors, which target specific cancer cell pathways, potentially offering a more targeted approach to treating lung cancer compared to traditional chemotherapy alone.
910111213Eligibility Criteria
Adults over 18 with advanced RAS-mutated NSCLC who have already tried standard treatments can join this trial. They should be relatively active and healthy (ECOG PS 0-1) with their major organs working well. Subprotocol A is specific to those with KRAS G12C mutations, while Subprotocol B is for broader RAS mutations.Inclusion Criteria
I have received the standard treatment for my cancer type and stage.
My cancer is advanced or has spread, cannot be removed by surgery, and has a specific KRAS G12C mutation.
My lung cancer is advanced or has spread and tests show a RAS mutation.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Exploration
Participants receive varying doses of RAS(ON) inhibitors to evaluate safety, tolerability, and pharmacokinetics
21 weeks
Regular visits for dose adjustments and monitoring
Dose Expansion
Participants receive the recommended Phase 2 dose to further evaluate antitumor activity
Up to 5 years
Regular visits for treatment and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 5 years
Participant Groups
The study tests new drugs called RMC-6291 and RMC-6236 in combination with standard cancer treatments like Cisplatin, Pemetrexed, Carboplatin, or Pembrolizumab. It aims to see how safe they are together and if they help against lung cancer.
3Treatment groups
Experimental Treatment
Group I: Subprotocol C: RAS G12D-mutated NSCLCExperimental Treatment6 Interventions
RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
Group II: Subprotocol B: RAS-mutated NSCLCExperimental Treatment5 Interventions
RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Group III: Subprotocol A: KRAS G12C-Mutated Solid TumorsExperimental Treatment6 Interventions
RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Carboplatin is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Paraplatin for:
- Ovarian cancer
- Testicular cancer
- Lung cancer
- Head and neck cancer
- Brain cancer
🇪🇺 Approved in European Union as Carboplatin for:
- Ovarian cancer
- Small cell lung cancer
🇨🇦 Approved in Canada as Carboplatin for:
- Ovarian cancer
- Small cell lung cancer
- Testicular cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope - DuarteDuarte, CA
University of California, San Diego Moores Cancer CenterSan Diego, CA
Stanford University - Stanford Cancer InstituteStanford, CA
New York University Langone HealthNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Revolution Medicines, Inc.Lead Sponsor
References
Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. [2015]Pemetrexed has established efficacy, and is the backbone for chemotherapy in patients with malignant pleural mesothelioma (MPM). An International Expanded Access Program provided >3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed plus platinum analogs (cisplatin or carboplatin) in 13 countries. In this article, we report the safety and efficacy data of MPM patients who were treated with single-agent pemetrexed (n = 812).
How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care. [2018]Cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb), together with newer chemotherapies, such as docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), paclitaxel (Taxol; Bristol-Myers Squibb), vinorelbine (Navelbine; GlaxoSmith-Kline, Philadelphia, http://www.gsk.com), pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, http://www.lilly.com), and gemcitabine (Gemzar; Eli Lilly and Company), have improved treatment outcomes in both advanced non-small cell lung cancer (NSCLC) and in the adjuvant/neoadjuvant setting. Newer systemic treatments for NSCLC, used in advanced stage IV management, are beginning to be studied in earlier stages of the disease, when treatment is better tolerated and potentially curative. Hopefully, newer agents with proven efficacies in advanced disease will enhance curability. Following the successful addition of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com) to carboplatin/paclitaxel in advanced disease, bevacizumab is now being incorporated into adjuvant and neoadjuvant trials. Trials in stage IB-IIIA patients will study neoadjuvant docetaxel/cisplatin/bevacizumab. The discovery that patients with exon 19 and 21 mutations in the epidermal growth factor receptor gene EGFR have around an 80% response rate to gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE, http:// www.astrazeneca-us.com) and that this response confers survival benefit indicates its potential utility for mutation-positive patients with advanced- and earlier-stage disease. Clinical characteristics, such as never smoking status and adenocarcinoma, and especially bronchioloalveolar carcinoma histological features, can also identify individuals likely to respond to EGFR tyrosine kinase inhibitors. Studies of neoadjuvant erlotinib (Tarceva; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com) in operable NSCLC are planned. One such study includes cisplatin and docetaxel. Effective development of active agents and disease management based on molecular profiling of lung tumors will change tomorrow's standard of care.
Safety profiles of non-small cell lung cancer patients treated with pemetrexed plus carboplatin: a real-world retrospective, observational, cohort study. [2018]Pemetrexed plus carboplatin (PCb) is a frequently used first-line treatment in advanced non-small cell lung cancer (NSCLC). This study examined the characteristics and safety profile of a NSCLC population treated with PCb area under the concentration-time curve 5 (PCb5) or 6 mg/mL•min (PCb6) under real-world conditions.
Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaïve patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study. [2022]In a large phase III study, cisplatin and pemetrexed had non-inferior efficacy and better tolerability compared with cisplatin and gemcitabine in chemonaïve patients with non-small cell lung cancer (NSCLC). The current analysis characterised the clinical benefit (i.e. survival) relative to clinical risk (i.e. drug-related toxicity) of the doublets.
Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients. [2021]The objective of this study was to evaluate the efficacy and safety of pemetrexed plus cisplatin/carboplatin in locally advanced or metastatic non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy.
Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. [2022]Pemetrexed-cisplatin is the only FDA-approved regimen for malignant pleural mesothelioma (MPM), and the impact on survival is modest. No drugs have been shown to improve survival as second-line therapy, yet vinorelbine and gemcitabine are prescribed based on the results of small phase II trials. To augment the existing limited data, we examined our institutional experience with vinorelbine and gemcitabine in patients with previously treated MPM.
Randomized phase II study of pemetrexed-cisplatin or docetaxel-cisplatin plus thoracic intensity-modulated radiation therapy in patients with stage IV lung adenocarcinoma. [2020]Systemic chemotherapy is the standard treatment modality for stage IV lung adenocarcinoma patients with EGFR wild-type or unknown mutation status. Recent years, there is increasing evidence showed that selected patients with stage IV disease could benefit from aggressive thoracic radiotherapy. Either pemetrexed or docetaxel, combined with cisplatin, can be used for patients with stage IV lung adenocarcinoma. However, no prospective trials have confirmed that Pem-Cis was superior to Doc-Cis in lung adenocarcinoma. In this randomized phase 2 trial, we evaluated survival outcomes, and toxicity of Pemetrexed-Cisplatin (arm A) or Docetaxel-Cisplatin (arm B) with concurrent IMRT to the primary tumor for stage IV lung adenocarcinoma patients with EGFR wild-type or unknown mutation status. Totally, 101 patients were randomly assigned (50 in arm A and 51 in arm B). Using an intention-to-treat analysis, one-year survival rates were 72.0% and 52.9%, respectively (P=0.020). Progression-free survival was also significantly improved in the arm A (median, 12.6 v 7.5 months, P=0.013). The incidence and severity of acute pneumonitis and esophagitis was similar between two arms. Although more of grade 3 or 4 anemia and thrombocytopenia in arm A, and higher rates grade 3 or 4 neutropenia, and leukopenia were observed in arm B. Pem-Cis first-line chemotherapy with concurrent radiation therapy for stage IV lung adenocarcinoma patients with EGFR wild-type or unknown mutation status represents a potential treatment option with acceptable toxicity and high overall survival rates.
Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. [2023]This post hoc analysis assessed the safety of pemetrexed and platinum in combination with pembrolizumab, including time-to-onset and time-to-resolution of all-cause any-grade and grade ≥3 adverse events (AEs) and renal AEs.
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. [2023]Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.
Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer. [2023]Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.
Cisplatin and Pemetrexed Have Distinctive Growth-inhibitory Effects in Monotherapy and Combination Therapy on KRAS-dependent A549 Lung Cancer Cells. [2021]Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer. However, its growth-inhibitory effects on KRAS-dependent lung cancer as monotherapy and combination therapy are not well understood. The aim of this study was to compare the effects of cisplatin and pemetrexed on A549 cells as mono- and combination therapies and elucidate the underlying mechanisms.
Rationale for non-platinum chemotherapy in advanced NSCLC. [2022]During the past decade, five new cytotoxic drugs have been introduced that are active against non-small-cell lung cancer (NSCLC). These agents include vinorelbine (Navelbine), paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine (Gemzar), and irinotecan (CPT-11, Camptosar). Used alone, these drugs display activity comparable to cisplatin. The combination of cisplatin and one of the newer drugs produces better survival than treatment with cisplatin (Platinol) alone. Randomized studies of chemotherapy regimens that include these newer drugs have demonstrated improved survival, fewer side effects, or both, compared with earlier standard combinations such as cisplatin/vindesine or cisplatin/etoposide. Docetaxel and perhaps some of the other newer drugs are of value for patients previously treated with platinum-containing regimens. Future studies should determine whether combinations of these newer drugs are superior to cisplatin-containing regimens. Although improved survival is the most important factor in defining the best regimen in non-small-cell lung cancer, additional considerations include patient tolerability, costs of administration, and the rationale for and ability to include noncytotoxic agents (such as inhibitors of signal transduction pathwriys or angiogenesis) into the therapeutic program.
Triplet combination chemotherapy and targeted therapy regimens. [2005]Current agents for the treatment of non-small-cell lung cancer include gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan (CPT-11, Camptosar). Experimental agents include pemetrexed (LY231514, Alimta) and tirapazamine. Molecular and biological therapies include angiogenesis inhibitors, epidermal growth factor receptor inhibitors, HER2/neu inhibitors, and inhibitors of ras activation and function. Doublet chemotherapy is currently the standard treatment for advanced non-small-cell lung cancer. In the past 2 years, randomized trials have shown that many of the new two-drug combinations used to treat non-small-cell lung cancer have equivalent efficacy. These combinations produce 1-year survival rates of about 35% and 2-year survival rates of about 15%. Toxicity rates vary but are sufficiently low as to make the development of three-drug combinations feasible. Preliminary studies from several phase I and II trials suggest that triplet therapy can improve survival beyond that of double therapy regimens.