Sotorasib + Chemotherapy for Lung Cancer

Recruiting at 1 trial location

Overseen By Ferdinandos Skoulidis, MD,PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, CYP3A4 inducers

Disqualifiers: Squamous NSCLC, Hematological malignancies, Cardiovascular disease, Gastrointestinal disease, others

Stay on Your Current Meds You can continue your current medications while participating

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase II, single-arm, open-label study evaluating the efficacy, safety and tolerability of neoadjuvant sotorasib in combination with cisplatin (or carboplatin) and pemetrexed chemotherapy for patients with surgically resectable stage IIA - IIIB (T3-T4/N2) (based on AJCC 8th edition), non-squamous NSCLC with a KRAS p.G12C mutation. The primary objective of the study is to determine whether neoadjuvant therapy with 4 cycles of at least one dose of sotorasib plus cisplatin (or carboplatin) and pemetrexed can be administered safely and result in improved MPR rate in patients with KRAS p.G12C-mutant non-squamous NSCLC compared with the historical control MPR rate for platinum-based chemotherapy alone.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications like strong inducers of CYP3A4, warfarin, and some others may need to be reviewed and approved by the principal investigator. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination of Sotorasib, Carboplatin, Cisplatin, and Pemetrexed for lung cancer?

Research shows that combining pemetrexed with either cisplatin or carboplatin has been effective in treating non-small cell lung cancer (NSCLC), leading to significant survival benefits. Additionally, the combination of pemetrexed and carboplatin has shown promising antitumor activity with mild side effects in advanced NSCLC. ^{1 2 3 4 5}

Is the combination of Sotorasib and chemotherapy safe for humans?

The combination of pemetrexed with cisplatin or carboplatin, which are chemotherapy drugs, has been studied for safety in lung cancer patients. Common side effects include fatigue, blood-related issues, digestive problems, and skin reactions. These studies suggest that while the treatment can be effective, it may also cause significant side effects. ^{2 6 7 8 9}

What makes the drug combination of Sotorasib and chemotherapy unique for lung cancer treatment?

The combination of Sotorasib with chemotherapy for lung cancer is unique because Sotorasib specifically targets a mutation in the KRAS gene, which is common in certain lung cancers, while the chemotherapy drugs like Carboplatin, Cisplatin, and Pemetrexed are used to kill cancer cells more broadly. This targeted approach, combined with traditional chemotherapy, may offer a more effective treatment option for patients with specific genetic profiles. ^{1 10 11 12 13}

Research Team

Ferdinandos Skoulidis, MD,PHD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults over 18 with stage IIA-IIIB non-squamous NSCLC, who haven't been treated before and have a KRAS p.G12C mutation. They must be fit for surgery, have good kidney function, an ECOG score of 0-1 (which means they're fully active or restricted in physically strenuous activity but can do light work), and no signs of stage IV cancer. Participants need to provide tissue samples, not be pregnant or breastfeeding, use effective contraception if applicable, and cannot have certain health issues that would interfere with the study.

Inclusion Criteria

My cancer is between stages IIA and select IIIB.

I can take pills and am willing to track my medication use daily.

My blood and liver tests are within normal ranges.

Exclusion Criteria

I agree not to donate sperm during my treatment.

I haven't needed strong antibiotics for infections in the last 2 weeks.

I have not had major surgery in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant sotorasib in combination with cisplatin (or carboplatin) and pemetrexed for 4 cycles

12 weeks

Surgery

Participants undergo surgical resection of the tumor

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Pemetrexed
• Sotorasib

Trial Overview The trial tests sotorasib combined with cisplatin (or carboplatin) and pemetrexed as pre-surgery treatment for lung cancer patients. The goal is to see if this combination improves the rate at which tumors shrink compared to historical data on chemotherapy alone. Patients will receive four cycles of treatment including at least one dose of sotorasib.

Participant Groups

Group I: Sotorasib in Combination with Cisplatin/Carboplatin and Pemetrexed Experimental Treatment 4 Interventions

4 cycles of at least one dose of sotorasib plus cisplatin (or carboplatin) and pemetrexed can be administered safely

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Amgen

Industry Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Findings from Research

In a randomized phase II trial involving 78 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of pemetrexed with carboplatin showed a median survival time of 10.4 months and a response rate of 39.5%, indicating it is an effective treatment option.

Both pemetrexed/cisplatin and pemetrexed/carboplatin combinations were well-tolerated, with manageable hematologic toxicities, suggesting that these treatments can be safely administered as first-line therapy for ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of pemetrexed combined with either cisplatin or carboplatin in untreated extensive-stage small-cell lung cancer. Socinski, MA., Weissman, C., Hart, LL., et al.[2015]

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 patients with metastatic non-small-cell lung cancer (NSCLC) expressing PD-L1 in ≥50% of tumor cells, pembrolizumab significantly improves progression-free and overall survival compared to traditional platinum-based chemotherapy.

Combining pembrolizumab with standard chemotherapy (pemetrexed and a platinum drug) enhances survival outcomes regardless of PD-L1 expression, indicating a broader efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. Wang, C., Kulkarni, P., Salgia, R.[2020]

Cisplatin-based chemotherapy has shown significant survival benefits for patients with non-small cell lung cancer, especially in resected disease, while carboplatin has not demonstrated a survival advantage in clinical trials.

Although cisplatin is more effective, it also has a higher toxicity profile, which must be carefully considered when deciding on treatment, especially for palliative care where quality of life is a priority.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin versus carboplatin in NSCLC: is there one "best" answer? Sanborn, RE.[2022]

Pemetrexed, when combined with carboplatin, has shown promising antitumor activity with mild toxicity in phase II clinical trials, but it can lead to serious adverse reactions such as toxic epidermal necrolysis, as seen in a reported case.

Supplementation with folic acid and vitamin B12 is recommended during pemetrexed treatment to help reduce the risk of hematological and gastrointestinal side effects, although severe skin reactions can still occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis related to pemetrexed and carboplatin with vitamin B12 and folic acid supplementation for advanced non-small cell lung cancer. Bosch-Barrera, J., Gaztañaga, M., Ceballos, J., et al.[2015]

In a meta-analysis of 486 patients with advanced non-squamous non-small cell lung cancer, the pemetrexed plus carboplatin regimen at 5 mg/min•mL (PCb5) showed a significantly lower incidence of treatment-emergent adverse events (TEAEs) compared to the 6 mg/min•mL (PCb6) regimen, including less thrombocytopenia, anemia, and fatigue.

Despite the differences in safety profiles, both PCb5 and PCb6 regimens demonstrated similar efficacy outcomes in terms of overall survival and progression-free survival, indicating that PCb5 may be a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. Okamoto, I., Schuette, WH., Stinchcombe, TE., et al.[2018]

In a study of 42 lung cancer patients receiving pemetrexed plus carboplatin, 19% experienced severe hematologic toxicities during the first cycle of chemotherapy, highlighting the significant risk associated with this treatment regimen.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) was found to significantly increase the risk of severe hematologic toxicities, suggesting that drug interactions may play a critical role in the toxicity experienced by patients, rather than renal function alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study. Kawazoe, H., Yano, A., Ishida, Y., et al.[2022]

Pemetrexed, an antifolate drug used for lung cancer treatment, can cause severe skin reactions like toxic epidermal necrolysis, as seen in a case involving a 58-year-old woman with a history of Sharp's syndrome.

While skin toxicity is a known side effect of pemetrexed, severe reactions are rare, highlighting the need for caution when administering this drug to patients with prior radiation therapy or existing skin conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis after pemetrexed and cisplatin for non-small cell lung cancer in a patient with sharp syndrome. Then, C., von Einem, JC., Müller, D., et al.[2015]

In a study involving 361 patients with advanced nonsquamous non-small-cell lung cancer, the combination of pemetrexed and carboplatin (Pem+Cb) did not show a significant advantage in progression-free survival without grade 4 toxicity compared to paclitaxel, carboplatin, and bevacizumab (Pac+Cb+Bev).

While both treatment regimens were generally well tolerated, Pem+Cb was associated with higher rates of grade 3/4 anemia and thrombocytopenia, whereas Pac+Cb+Bev had more cases of grade 3/4 neutropenia and alopecia, indicating differing toxicity profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. Zinner, RG., Obasaju, CK., Spigel, DR., et al.[2022]

Cisplatin combined with other agents like vinblastine or etoposide shows promise as an effective pre-radiotherapy treatment for locally advanced non-small cell lung cancer (NSCLC), but optimal scheduling is still being researched.

In a study of 170 patients, concurrent chemotherapy with carboplatin and radiation led to increased toxicity, including significantly higher rates of neutropenia and thrombocytopenia, indicating that while this approach may improve treatment efficacy, it also raises safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scheduling of chemotherapy and radiotherapy in locally advanced non-small cell lung cancer. Bishop, JF.[2019]

Cisplatin combined with either a vinca alkaloid or etoposide is highly effective in reducing mortality for patients with non-small cell lung cancer, as shown in meta-analyses comparing chemotherapy to supportive care.

Recent studies indicate that combining cisplatin-based chemotherapy with new agents and radiotherapy can significantly prolong survival and improve outcomes for patients with locally advanced non-small cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy for non-small cell lung cancer]. Shinkai, T., Saijo, N.[2018]

In a study of 28 patients with advanced non-small cell lung cancer (NSCLC), the combination of carboplatin, vindesine, and 5-fluorouracil/leucovorin, along with 13-cis retinoic acid, resulted in a 39% overall response rate, indicating that this treatment regimen is effective for some patients.

The treatment was associated with manageable toxicity, with 46% of patients experiencing severe hematological side effects, suggesting that while the therapy is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin, vindesine, 5-fluorouracil-leucovorin and 13-cis retinoic acid in the treatment of advanced non-small cell lung cancer. A phase II study. Recchia, F., De Filippis, S., Pompili, PL., et al.[2013]

Pemetrexed, a multitargeted antifolate agent, has shown comparable overall survival to docetaxel in second-line treatment for advanced non-small cell lung cancer (NSCLC), with a better toxicity profile, making it a safer option for patients.

In nonsquamous NSCLC, pemetrexed combined with folic acid and vitamin B12 significantly improved median survival to 9.3 months compared to 8.0 months with docetaxel, highlighting its efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in second line of non-small cell lung cancer. Barata, F.[2015]

References

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

Randomized phase II trial of pemetrexed combined with either cisplatin or carboplatin in untreated extensive-stage small-cell lung cancer. [2015]

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

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

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

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. [2020]

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

Cisplatin versus carboplatin in NSCLC: is there one "best" answer? [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis related to pemetrexed and carboplatin with vitamin B12 and folic acid supplementation for advanced non-small cell lung cancer. [2015]

6. England pubmed.ncbi.nlm.nih.gov

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. [2018]

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

Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis after pemetrexed and cisplatin for non-small cell lung cancer in a patient with sharp syndrome. [2015]

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

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. [2022]

10. Ireland pubmed.ncbi.nlm.nih.gov

Scheduling of chemotherapy and radiotherapy in locally advanced non-small cell lung cancer. [2019]

11. Japan pubmed.ncbi.nlm.nih.gov

[Chemotherapy for non-small cell lung cancer]. [2018]

12. Italy pubmed.ncbi.nlm.nih.gov

Carboplatin, vindesine, 5-fluorouracil-leucovorin and 13-cis retinoic acid in the treatment of advanced non-small cell lung cancer. A phase II study. [2013]

13. Spain pubmed.ncbi.nlm.nih.gov

Pemetrexed in second line of non-small cell lung cancer. [2015]