Chemotherapy + Immunotherapy for Mesothelioma

Recruiting at 40 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, NSAIDs

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

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: 10

Duration: 12 weeks

66 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had prior systemic therapy for peritoneal mesothelioma, and you should not use NSAIDs like ibuprofen around the time of pemetrexed administration if your creatinine clearance is between 45 and 79 mL/min. Also, you should not be on immunosuppressive medication within 2 weeks before starting the trial, except for certain low-dose or specific medications. It's best to discuss your current medications with the trial team.

What data supports the idea that Chemotherapy + Immunotherapy for Mesothelioma is an effective treatment?

The available research shows that combining pemetrexed with cisplatin, which are part of the chemotherapy regimen, is more effective than using cisplatin alone for treating mesothelioma. In a large study, patients who received both pemetrexed and cisplatin lived longer on average (12.1 months) compared to those who received only cisplatin (9.3 months). Additionally, the combination treatment improved the quality of life and lung function for patients. This suggests that the chemotherapy part of the Chemotherapy + Immunotherapy treatment is effective for mesothelioma. ^{1 2 3 4 5}

What safety data is available for the chemotherapy and immunotherapy treatment for mesothelioma?

The safety data for the chemotherapy treatment involving pemetrexed (Alimta) combined with cisplatin or carboplatin for malignant pleural mesothelioma includes several adverse events. Pemetrexed causes myelosuppression, with common side effects such as neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. Additional reported toxicities include scleroderma-like changes in the lower legs and urticarial vasculitis. Patients are advised to take oral folic acid and vitamin B12 injections to reduce severe toxicities, and corticosteroids to minimize skin rashes. The treatment has been evaluated in various studies, including a phase III trial and an International Expanded Access Program, which provided safety and efficacy data for over 3000 patients. ^{1 2 3 6 7}

Is the drug combination of Carboplatin and Pemetrexed promising for treating mesothelioma?

Yes, the combination of Carboplatin and Pemetrexed is promising for treating mesothelioma. Studies show that this drug combination can be effective and well-tolerated, with some patients experiencing significant positive responses. It is considered a feasible alternative to other standard treatments. ^{1 8 9 10 11}

What is the purpose of this trial?

This phase II trial compares the usual treatment alone (carboplatin, pemetrexed, and bevacizumab) to using immunotherapy (atezolizumab) plus the usual treatment in treating patients with peritoneal mesothelioma. The usual treatment consists of surgery or chemotherapy. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make deoxyribonucleic acid and may kill cancer cells. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab with usual treatment may work better than usual treatment alone.

Research Team

Aaron S Mansfield, MD

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

Adults with untreated malignant peritoneal mesothelioma, without a history of central nervous system disease, significant bleeding disorders, or severe heart conditions. They must have functioning major organs and no autoimmune diseases (with some exceptions like controlled thyroid issues). Women must not be pregnant or nursing and agree to use birth control.

Inclusion Criteria

Your AST and ALT levels should not be more than three times the upper limit of normal.

Your disease must be able to be measured using specific guidelines.

I haven't had a biopsy or minor surgery, except for a device placement, in the last 7 days.

Exclusion Criteria

I agree to use effective birth control during the study due to the risk of birth defects.

Physicians should consider whether any of the following may render the patient inappropriate for this protocol: Psychiatric illness which would prevent the patient from giving informed consent

I do not have any uncontrolled conditions like infection, diabetes, or heart disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive chemotherapy with or without immunotherapy every 21 days for up to 4 cycles, followed by surgery and HIPEC if eligible

12 weeks

4 visits (in-person)

Maintenance Therapy

Patients not eligible for surgery may receive maintenance therapy every 21 days in the absence of disease progression or unacceptable toxicity

Variable

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 6 months

Treatment Details

Interventions

• Atezolizumab
• Bevacizumab
• Carboplatin
• Pemetrexed

Trial Overview The trial is testing the effectiveness of adding immunotherapy (atezolizumab) to the usual treatment for peritoneal mesothelioma which includes surgery and chemotherapy drugs like carboplatin and pemetrexed. The goal is to see if atezolizumab helps the immune system fight cancer better than standard treatments alone.

Participant Groups

Group I: Arm I (carboplatin, pemetrexed, bevacizumab, atezolizumab) Experimental Treatment 9 Interventions

Patients receive atezolizumab IV over 30-60 minutes, bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients then undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1 of each maintenance therapy cycle. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, PET scan, and collection of blood and tissue samples throughout the study.

Group II: Arm II (carboplatin, pemetrexed, bevacizumab) Active Control 8 Interventions

Patients receive bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients then undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive bevacizumab IV over 30-90 minutes with or without atezolizumab IV over 30-60 minutes on day 1 of each maintenance therapy cycle at the discretion of the investigator. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, PET scan, and collection of blood and tissue samples throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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, 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 51 patients with malignant pleural mesothelioma, both pemetrexed with carboplatin (AC) and pemetrexed with cisplatin (AP) were found to be effective neoadjuvant chemotherapy regimens, with similar rates of disease control and surgical resection (81% for AC and 79% for AP).

However, the AP regimen was associated with a higher incidence of severe side effects, such as grade 3 anemia and increased fatigue, which could negatively affect patients' overall health and their ability to undergo surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus carboplatin or cisplatin as neoadjuvant treatment of operable malignant pleural mesothelioma (MPM). Pasello, G., Marulli, G., Polo, V., et al.[2015]

In a phase II study involving 62 patients with unresectable malignant pleural mesothelioma (MPM), the combination of carboplatin and pemetrexed showed significant activity, with 29% of patients achieving a confirmed partial response and 54.9% maintaining stable disease.

The median overall survival for patients was 14 months, with a notable difference in survival based on histologic subtype, highlighting the efficacy of this chemotherapy regimen as a first-line treatment option for MPM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study. Katirtzoglou, N., Gkiozos, I., Makrilia, N., et al.[2015]

Pemetrexed, especially when combined with cisplatin, has shown significantly higher efficacy in treating malignant pleural mesothelioma (MPM) compared to cisplatin alone, with a response rate of 41.3% and a median survival of 12.1 months versus 9.3 months for cisplatin.

In addition to improved survival rates, the pemetrexed/cisplatin combination also resulted in better quality of life and pulmonary function for patients, highlighting its potential as a more effective treatment option for MPM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in malignant pleural mesothelioma. Gatzemeier, U.[2015]

Pemetrexed, a treatment for malignant pleural mesothelioma and non-small cell lung cancer, has been associated with a new toxicity resembling scleroderma, as seen in two cases involving painful induration and edema of the lower extremities.

This adverse effect can be mistaken for erysipelas due to similar symptoms, but it lacks fever; recognizing this toxicity is crucial for timely diagnosis and management, and folate and vitamin B12 supplementation may help reduce its incidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pemetrexed-induced scleroderma-like changes in the lower legs]. Corbaux, C., Marie, J., Meraud, JP., et al.[2015]

Pemetrexed is an FDA-approved anti-folate agent used to treat malignant pleural mesothelioma and previously treated non-small cell lung cancer, showing efficacy in these patient populations.

In clinical trials, rash occurred in 17-22% of patients treated with pemetrexed, and this report highlights a specific case of rash due to urticarial vasculitis, contributing to the understanding of pemetrexed's side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed-associated urticarial vasculitis. Lopes, G., Vincek, V., Raez, LE.[2015]

A case report highlights a patient with malignant pleural mesothelioma achieving a complete pathological response after receiving four cycles of preoperative chemotherapy with carboplatin and pemetrexed, followed by surgery.

The carboplatin plus pemetrexed regimen was well tolerated, showing no severe hematological toxicity, suggesting it could be a safer alternative to the standard cisplatin plus pemetrexed treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pathological complete response after preoperative chemotherapy with carboplatin and pemetrexed in malignant pleural mesothelioma: A case report. Pasello, G., Altavilla, G., Bonanno, L., et al.[2021]

The EMPHACIS trial, a phase III study involving pemetrexed combined with cisplatin, demonstrated significant improvement in survival for patients with malignant pleural mesothelioma compared to standard treatments.

Supplementation with low-dose folic acid and vitamin B12 significantly reduced the toxicity associated with the pemetrexed/cisplatin regimen, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma. Manegold, C.[2019]

Two cases of anaphylactic reactions to cisplatin in patients treated for pleural mesothelioma highlight the potential for hypersensitivity to platinum-based chemotherapy, occurring after multiple treatment cycles.

Skin tests and flow cytometry were effective methods for confirming the diagnosis of hypersensitivity, indicating their utility in managing patients undergoing platinum-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Investigation of allergic reactions to platinum salts]. Touraine, F., Sainte Laudy, J., Boumediene, A., et al.[2019]

In a large study involving 1704 chemonaïve patients with malignant pleural mesothelioma, pemetrexed combined with cisplatin showed a higher response rate (26.3%) compared to pemetrexed with carboplatin (21.7%).

Both treatment combinations resulted in similar 1-year survival rates (63.1% for cisplatin and 64.0% for carboplatin) and median time to disease progression, indicating that both regimens are effective options for patients not eligible for curative surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. Santoro, A., O'Brien, ME., Stahel, RA., et al.[2015]

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

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

3. Greece pubmed.ncbi.nlm.nih.gov

Pemetrexed plus carboplatin or cisplatin as neoadjuvant treatment of operable malignant pleural mesothelioma (MPM). [2015]

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

Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study. [2015]

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

Pemetrexed in malignant pleural mesothelioma. [2015]

6. France pubmed.ncbi.nlm.nih.gov

[Pemetrexed-induced scleroderma-like changes in the lower legs]. [2015]

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

Pemetrexed-associated urticarial vasculitis. [2015]

8. China pubmed.ncbi.nlm.nih.gov

A pathological complete response after preoperative chemotherapy with carboplatin and pemetrexed in malignant pleural mesothelioma: A case report. [2021]

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

Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma. [2019]

10. France pubmed.ncbi.nlm.nih.gov

[Investigation of allergic reactions to platinum salts]. [2019]

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

Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. [2015]