RAS Inhibitors + Standard Treatments for Lung Cancer

Recruiting at 62 trial locations

Overseen By Revolution Medicines

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Revolution Medicines, Inc.

Disqualifiers: CNS tumors, Impaired GI function, others

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

Compensation: Varies

Number of Visits: Unknown

484 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 5 6 7 8}

What 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. ^{9 10 11 12 13}

Research Team

Revolution Medicines

Principal Investigator

Revolution Medicines

Eligibility 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.

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

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Pembrolizumab
• Pemetrexed
• RMC-6236
• RMC-6291

Trial Overview 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.

Participant Groups

Group I: Subprotocol C: RAS G12D-mutated NSCLC Experimental Treatment 6 Interventions

RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).

Group II: Subprotocol B: RAS-mutated NSCLC Experimental Treatment 5 Interventions

RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)

Group III: Subprotocol A: KRAS G12C-Mutated Solid Tumors Experimental Treatment 6 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

Who Is Running the Clinical Trial?

Revolution Medicines, Inc.

Lead Sponsor

Trials

14

Recruited

4,500+

Findings from Research

In a study involving 812 patients with malignant pleural mesothelioma (MPM), single-agent pemetrexed showed promising efficacy, with a median time to progressive disease of 6.0 months for chemonaïve patients and an overall response rate of 10.5%.

The treatment was well-tolerated, exhibiting mild hematologic toxicity, primarily neutropenia, in less than 18% of patients, indicating a favorable safety profile for pemetrexed in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. Taylor, P., Castagneto, B., Dark, G., et al.[2015]

Cisplatin and carboplatin, along with newer chemotherapies like docetaxel and bevacizumab, have significantly improved treatment outcomes for advanced non-small cell lung cancer (NSCLC) and are now being tested in earlier stages for potentially curative effects.

Patients with specific mutations in the EGFR gene show an 80% response rate to gefitinib, highlighting the importance of molecular profiling in tailoring treatments for NSCLC, which could lead to better management and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care. Kris, MG.[2018]

In a study of 820 patients with advanced non-small cell lung cancer (NSCLC) treated with either pemetrexed plus carboplatin (PCb5 or PCb6), the safety profiles showed similar rates of neutropenia, but higher rates of anemia and thrombocytopenia in the PCb6 cohort compared to PCb5.

The study highlighted that older patients (≥70 years) receiving PCb6 had a significantly higher incidence of neutropenia, suggesting that age and treatment regimen may influence the safety outcomes of chemotherapy in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profiles of non-small cell lung cancer patients treated with pemetrexed plus carboplatin: a real-world retrospective, observational, cohort study. Chen, L., San Antonio, B., Yan, Y., et al.[2018]

In a study involving 1669 patients with non-small cell lung cancer (NSCLC), treatment with cisplatin and pemetrexed resulted in significantly longer survival without severe drug-related toxicity compared to cisplatin and gemcitabine, indicating a better clinical benefit-to-risk profile.

For patients with non-squamous NSCLC, cisplatin and pemetrexed not only improved survival without grade 3 or 4 toxicity but also showed superior outcomes in terms of survival without grade 4 toxicity, highlighting its effectiveness and tolerability in this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Scagliotti, GV., Park, K., Patil, S., et al.[2022]

In a study of 53 patients with advanced non-small cell lung cancer (NSCLC) who had previously undergone platinum-based chemotherapy, treatment with pemetrexed plus cisplatin or carboplatin resulted in a median overall survival of 10 months and a median progression-free survival of 6 months.

The treatment was generally well-tolerated, with only a small percentage of patients experiencing severe side effects, such as grade 3 or 4 leukopenia and thrombocytopenia, indicating that pemetrexed combined with platinum-based drugs can be a safe option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients. Zhang, GZ., Jiao, SC., Meng, ZT.[2021]

In a study of 60 patients with previously treated malignant pleural mesothelioma, vinorelbine and gemcitabine showed a very low response rate of only 2%, indicating limited efficacy as second-line therapies.

Despite the low response rate, 46% of patients experienced stable disease, suggesting that these drugs may still have a role in treatment, although their overall impact on survival remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Zauderer, MG., Kass, SL., Woo, K., et al.[2022]

In a randomized phase 2 trial involving 101 patients with stage IV lung adenocarcinoma, the combination of Pemetrexed and Cisplatin (Pem-Cis) showed a significantly higher one-year survival rate of 72.0% compared to 52.9% for Docetaxel and Cisplatin (Doc-Cis).

Patients receiving Pem-Cis also experienced longer progression-free survival (12.6 months) compared to those on Doc-Cis (7.5 months), indicating that Pem-Cis may be a more effective first-line treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of pemetrexed-cisplatin or docetaxel-cisplatin plus thoracic intensity-modulated radiation therapy in patients with stage IV lung adenocarcinoma. Su, SF., Li, M., Geng, YC., et al.[2020]

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., et al.[2023]

In a phase III study involving 1,725 patients with advanced non-small-cell lung cancer (NSCLC), the combination of cisplatin and pemetrexed showed noninferior overall survival compared to cisplatin and gemcitabine, with both regimens resulting in a median survival of 10.3 months.

Cisplatin/pemetrexed demonstrated better tolerability, with significantly lower rates of severe side effects like neutropenia and anemia, although it was associated with higher rates of nausea, making it a more convenient treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. Scagliotti, GV., Parikh, P., von Pawel, J., et al.[2023]

In a study of 1,725 patients with advanced non-small-cell lung cancer (NSCLC), the combination of cisplatin and pemetrexed showed noninferior overall survival compared to cisplatin and gemcitabine, with both regimens resulting in a median survival of 10.3 months.

Cisplatin/pemetrexed demonstrated better tolerability, with significantly lower rates of severe side effects like neutropenia and anemia, although it was associated with higher rates of nausea, making it a more convenient option for patients compared to cisplatin/gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer. Scagliotti, GV., Parikh, P., von Pawel, J., et al.[2023]

Cisplatin alone was found to be the most effective treatment for A549 lung cancer cells, showing the highest cytotoxicity compared to both pemetrexed alone and the combination of cisplatin and pemetrexed.

The combination therapy of cisplatin and pemetrexed induced significant autophagy and reduced cellular senescence, but was less effective than cisplatin monotherapy in inhibiting KRAS-dependent pathways and promoting cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin and Pemetrexed Have Distinctive Growth-inhibitory Effects in Monotherapy and Combination Therapy on KRAS-dependent A549 Lung Cancer Cells. Mohiuddin, M., Kasahara, K.[2021]

Five new cytotoxic drugs have been introduced for treating non-small-cell lung cancer (NSCLC), showing comparable activity to cisplatin when used alone, and improved survival when combined with cisplatin.

Randomized studies indicate that these newer drugs not only enhance survival rates but also reduce side effects compared to older chemotherapy regimens, suggesting they are valuable options for patients, including those previously treated with platinum-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale for non-platinum chemotherapy in advanced NSCLC. Murren, JR.[2022]

Current standard treatment for advanced non-small-cell lung cancer involves doublet chemotherapy, which has shown 1-year survival rates of approximately 35% and 2-year survival rates of about 15%.

Preliminary studies indicate that triplet therapy may enhance survival rates compared to double therapy, with toxicity rates being low enough to support the development of these three-drug combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination chemotherapy and targeted therapy regimens. Bunn, PA.[2005]

References

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

Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. [2015]

2. England pubmed.ncbi.nlm.nih.gov

How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Safety profiles of non-small cell lung cancer patients treated with pemetrexed plus carboplatin: a real-world retrospective, observational, cohort study. [2018]

4. England pubmed.ncbi.nlm.nih.gov

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]

5. England pubmed.ncbi.nlm.nih.gov

Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients. [2021]

6. Ireland pubmed.ncbi.nlm.nih.gov

Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. [2022]

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

Randomized phase II study of pemetrexed-cisplatin or docetaxel-cisplatin plus thoracic intensity-modulated radiation therapy in patients with stage IV lung adenocarcinoma. [2020]

8. Ireland pubmed.ncbi.nlm.nih.gov

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]

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

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. [2023]

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

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer. [2023]

11. Greece pubmed.ncbi.nlm.nih.gov

Cisplatin and Pemetrexed Have Distinctive Growth-inhibitory Effects in Monotherapy and Combination Therapy on KRAS-dependent A549 Lung Cancer Cells. [2021]

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

Rationale for non-platinum chemotherapy in advanced NSCLC. [2022]

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

Triplet combination chemotherapy and targeted therapy regimens. [2005]