Pembrolizumab + Chemotherapy for Mesothelioma

Overseen by Corey Langer, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Abramson Cancer Center of the University of Pennsylvania

Must not be taking: Immunosuppressants, Steroids, Monoclonal antibodies, others

Disqualifiers: Immunodeficiency, Active TB, Autoimmune, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment for patients with lung lining cancer. It combines an immune-boosting drug and precise surgery with standard treatments to see if it works better.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on immunosuppressive therapy or chronic systemic steroids above a certain dose, and you must not have had recent chemotherapy, targeted therapy, or radiation therapy within 2 weeks before starting the trial.

What data supports the effectiveness of the drug combination of pembrolizumab, chemotherapy, and other agents for treating mesothelioma?

Research shows that pemetrexed, when used alone or with cisplatin, has been effective in treating mesothelioma, improving response rates and survival times. The combination of pemetrexed and cisplatin has shown better outcomes compared to cisplatin alone, with increased median survival from 9.3 to 12.1 months. ^{1 2 3 4 5}

Is the combination of pembrolizumab and chemotherapy safe for treating mesothelioma?

The combination of pemetrexed and cisplatin, which is part of the chemotherapy regimen for mesothelioma, has been studied for safety. Common side effects include low blood cell counts, tiredness, nausea, and vomiting. Patients are advised to take vitamins and steroids to help reduce severe side effects. ^{1 6 7 8 9}

How is the drug combination of pembrolizumab, cisplatin, and pemetrexed unique for treating mesothelioma?

This drug combination is unique because it adds pembrolizumab, an immune checkpoint inhibitor that helps the immune system fight cancer, to the standard chemotherapy drugs cisplatin and pemetrexed, potentially improving survival rates for patients with advanced pleural mesothelioma compared to chemotherapy alone. ^{1 9 10 11 12}

Research Team

Corey Langer, MD

Principal Investigator

University of Pennsylvania Abramson Cancer Center

Eligibility Criteria

This trial is for adults with malignant pleural mesothelioma who are in good physical condition, have proper organ function, and can provide a recent tumor tissue sample. They must not have other active cancers or serious health conditions that could interfere with the study, no recent immunosuppressive treatments, and agree to use contraception.

Inclusion Criteria

I agree to provide a recent biopsy sample or an archived one with approval.

I can carry out all my usual activities without help.

I agree to use or continue using contraception during and up to 120 days after the study.

Exclusion Criteria

I have been diagnosed with interstitial lung disease.

I have had pneumonitis treated with steroids or have it now.

Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab in combination with chemotherapy and undergo image-guided surgery

up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days for serious adverse events

Long-term follow-up

Participants are assessed for overall survival and progression-free survival

up to 2 years

Treatment Details

Interventions

• Cisplatin (Alkylating agents)
• Indocyanine Green (ICG) Image-Guided Surgery (Procedure)
• Pembrolizumab (Monoclonal Antibodies)
• Pemetrexed (Anti-metabolites)

Trial Overview The trial tests pembrolizumab (an immune therapy) combined with chemotherapy (cisplatin and pemetrexed) and image-guided surgery using Indocyanine Green (ICG). It aims to assess safety, feasibility, and initial effectiveness of this combination treatment approach.

Participant Groups

Group I: Pembrolizumab with image-guided surgery and chemotherapy Experimental Treatment 4 Interventions

Cisplatin is already approved in Canada, Japan for the following indications:

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Abramson Cancer Center of the University of Pennsylvania

Lead Sponsor

Trials

360

Recruited

108,000+

Dr. Robert H. Vonderheide

Abramson Cancer Center of the University of Pennsylvania

Chief Executive Officer since 2017

DPhil in Immunology from Oxford University, MD from Harvard Medical School

Dr. Lawrence N. Shulman

Abramson Cancer Center of the University of Pennsylvania

Chief Medical Officer since 2017

MD from Harvard Medical School

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Dr. Robert H. Vonderheide

Abramson Cancer Center at Penn Medicine

Chief Executive Officer since 2017

MD from Harvard Medical School

Dr. Bonnie Ky

Abramson Cancer Center at Penn Medicine

Chief Medical Officer

MD, MSCE from University of Pennsylvania

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]

Pemetrexed disodium is an effective antimetabolite that works by inhibiting key enzymes involved in tumor growth, showing a 14.5% response rate as a single agent in previously untreated mesothelioma patients.

Combining pemetrexed with cisplatin or carboplatin has resulted in promising regression rates, with a notable 40% partial response rate in a trial involving 25 mesothelioma patients, indicating enhanced efficacy when used in combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alimta (pemetrexed disodium): a multitargeted antifolate for the treatment of mesothelioma. Green, MR.[2019]

In a study involving 567 patients with malignant mesothelioma, pemetrexed alone or in combination with cisplatin or carboplatin showed overall response rates of 16%, 24%, and 18%, respectively, indicating that these treatments are effective options for managing this condition.

Pemetrexed alone was found to be less toxic to the blood compared to the combination therapies, suggesting it may be a safer option for patients, especially those who have already undergone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in the treatment of malignant mesothelioma: results from an expanded access program in Germany. Reck, M., Stahel, RA., von Pawel, J., et al.[2015]

Pemetrexed, often combined with cisplatin or carboplatin, is the most widely studied treatment for malignant pleural mesothelioma (MPM) in Europe, with around 1500 patients enrolled in an Extended Access Program, showing improved survival rates compared to other treatments.

The largest randomized trial indicated that combining pemetrexed with cisplatin improved median survival from 9.3 to 12.1 months, highlighting its efficacy in treating MPM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview on ongoing or planned clinical trials in Europe. Favaretto, A.[2015]

Malignant mesothelioma is a challenging cancer to treat, and while newer agents like gemcitabine and pemetrexed show some promise, their impact on survival is minimal for patients with unresectable disease.

A phase III trial involving over 450 patients is underway to compare the effectiveness of cisplatin alone versus a combination of pemetrexed and cisplatin, with preliminary phase II results indicating a 15% partial response rate for pemetrexed alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of gemcitabine and pemetrexed (Alimta) in the management of patients with malignant mesothelioma. Green, MR.[2019]

Pemetrexed, when combined with cisplatin, significantly improves median survival in patients with malignant pleural mesothelioma, with a median survival of 12.1 months compared to 9.3 months for cisplatin alone, based on a phase III trial involving 448 patients.

The drug works by inhibiting key enzymes involved in DNA synthesis, but it can cause side effects like myelosuppression, neutropenia, and fatigue, necessitating supportive care with folic acid, vitamin B12, and corticosteroids during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summaries: pemetrexed (Alimta). Hazarika, M., White, RM., Johnson, JR., et al.[2022]

In a study of 903 patients with malignant pleural mesothelioma (MPM), pemetrexed combined with cisplatin was found to be generally well tolerated, with a low treatment-associated death rate of 0.8% and an interstitial lung disease (ILD) incidence of 0.9%.

The overall response rate to treatment was 25%, and the six-month survival rate was estimated at 75.9%, indicating that pemetrexed is effective in managing MPM, consistent with previous clinical trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of pemetrexed in patients with malignant pleural mesothelioma based on all-case drug-registry study. Kuribayashi, K., Voss, S., Nishiuma, S., et al.[2015]

The recommended dose of pemetrexed combined with cisplatin (Pem/Cis) was established as effective for treating malignant pleural mesothelioma (MPM) in a Phase I/II study involving 19 Japanese patients, with a partial response rate of 36.8%.

The treatment showed an acceptable safety profile, although some patients experienced significant toxicities like neutropenia and one drug-related death due to worsening pneumonia, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pemetrexed in combination with cisplatin for malignant pleural mesothelioma: a phase I/II study in Japanese patients. Nakagawa, K., Yamazaki, K., Kunitoh, H., et al.[2022]

In a study of 146 patients with malignant pleural mesothelioma, the combination of cis/carboplatin plus gemcitabine showed similar median survival rates (11.0 months) compared to cis/carboplatin plus pemetrexed (12.0 months), indicating that both treatment regimens are comparably effective.

Both treatment combinations were well tolerated with similar side effects, suggesting that cis/carboplatin plus gemcitabine is a safe alternative for patients, warranting further investigation in larger randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness and safety of platinum-based pemetrexed and platinum-based gemcitabine treatment in patients with malignant pleural mesothelioma. Ak, G., Metintas, S., Akarsu, M., et al.[2022]

In a phase 3 trial involving 440 patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy significantly improved overall survival, with a median survival of 17.3 months compared to 16.1 months for chemotherapy alone.

While the combination treatment was effective, it also led to a higher incidence of serious adverse events, with 27% of patients experiencing grade 3 or 4 adverse events compared to 15% in the chemotherapy-only group, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Chu, Q., Perrone, F., Greillier, L., et al.[2023]

In a phase 2 trial involving 120 patients, the combination of standard chemotherapy (platinum and pemetrexed) with pembrolizumab (CP + pembro) showed improved median survival (19.8 months) and overall response rate (47%) compared to chemotherapy alone (8.9 months and 19%, respectively).

The addition of pembrolizumab to chemotherapy was found to be tolerable, and although the progression-free survival was similar between the treatment arms, the combination therapy demonstrated better outcomes, leading to the continuation of research in a phase 3 trial with results expected in 2023.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brief Report: Canadian Cancer Trials Group IND.227: A Phase 2 Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma (NCT02784171). Piccirillo, MC., Chu, Q., Bradbury, P., et al.[2023]

The combination of pemetrexed and cisplatin has been shown to induce high response rates in malignant pleural mesothelioma (MPM), a type of lung cancer that has been resistant to chemotherapy.

The review highlights a key phase III clinical trial that led to the FDA approval of pemetrexed, indicating its significant role in the treatment of MPM, with ongoing research expected to further clarify its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma. Goudar, RK.[2022]

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. Ireland pubmed.ncbi.nlm.nih.gov

Alimta (pemetrexed disodium): a multitargeted antifolate for the treatment of mesothelioma. [2019]

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

Pemetrexed in the treatment of malignant mesothelioma: results from an expanded access program in Germany. [2015]

4. Ireland pubmed.ncbi.nlm.nih.gov

Overview on ongoing or planned clinical trials in Europe. [2015]

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

The evolving role of gemcitabine and pemetrexed (Alimta) in the management of patients with malignant mesothelioma. [2019]

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

FDA drug approval summaries: pemetrexed (Alimta). [2022]

7. Ireland pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of pemetrexed in patients with malignant pleural mesothelioma based on all-case drug-registry study. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pemetrexed in combination with cisplatin for malignant pleural mesothelioma: a phase I/II study in Japanese patients. [2022]

9. England pubmed.ncbi.nlm.nih.gov

The effectiveness and safety of platinum-based pemetrexed and platinum-based gemcitabine treatment in patients with malignant pleural mesothelioma. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. [2023]

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

Brief Report: Canadian Cancer Trials Group IND.227: A Phase 2 Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma (NCT02784171). [2023]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma. [2022]