Pemetrexed + Cisplatin +/- Cediranib for Mesothelioma

Recruiting at 260 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

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

Compensation: Varies

Number of Visits: 18

117 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase I/II trial is studying the side effects and best dose of cediranib maleate when given together with pemetrexed disodium and cisplatin and to see how well it works in treating patients with malignant pleural mesothelioma. Drugs used in chemotherapy, pemetrexed disodium and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving pemetrexed disodium and cisplatin together with cediranib maleate may kill more tumor cells.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not be on any medication that affects kidney function or has a high risk of causing heart rhythm problems. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Pemetrexed and Cisplatin for treating mesothelioma?

Research shows that the combination of Pemetrexed and Cisplatin is effective for treating mesothelioma, with studies reporting encouraging response rates and disease stabilization. For example, one study found a 40% partial response rate in patients, and another highlighted prolonged disease control in a case report. ^{1 2 3 4 5}

Is the combination of Pemetrexed and Cisplatin safe for treating mesothelioma?

The combination of Pemetrexed and Cisplatin is generally considered safe for treating mesothelioma, but it can cause side effects like low blood cell counts, tiredness, and nausea. Patients are advised to take vitamins and steroids to help reduce these side effects. ^{6 7 8 9 10}

What makes the drug Pemetrexed + Cisplatin +/- Cediranib unique for treating mesothelioma?

The combination of Pemetrexed and Cisplatin is a standard treatment for mesothelioma, known for its effectiveness in shrinking tumors. Adding Cediranib, which is not part of the standard regimen, may enhance the treatment by targeting blood vessel growth in tumors, potentially improving outcomes. ^{1 6 10 11 12}

Research Team

Anne S Tsao

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for patients with malignant pleural mesothelioma who haven't had systemic therapy for it. They can have had previous neoadjuvant or adjuvant treatment if it was over 6 months ago and didn't include cediranib. Participants need proper organ function, no plans for surgery, not pregnant or nursing, and must use effective contraception.

Inclusion Criteria

I can take care of myself and am up and about more than 50% of my waking hours.

My hemoglobin level is at least 9.0 g/dl.

My kidneys are functioning well.

Exclusion Criteria

I have no cancer history except for certain skin cancers, early-stage cancers in remission, or any cancer I've been free from for 5 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Patients receive pemetrexed disodium and cisplatin IV on day 1 and cediranib maleate PO daily on days 1-21. Treatment repeats every 21 days for 6 courses.

18 weeks

6 visits (in-person)

Phase II Treatment

Patients are randomized to receive either cediranib maleate or placebo with pemetrexed disodium and cisplatin. Treatment repeats every 21 days for 6 courses.

18 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up every 6 months for 2 years, then at 3 years.

3 years

Every 6 months for 2 years, then at 3 years

Treatment Details

Interventions

• Cediranib Maleate
• Cisplatin
• Pemetrexed Disodium

Trial Overview The study tests the effectiveness of combining pemetrexed disodium and cisplatin with cediranib maleate versus without it in treating mesothelioma. It aims to find the best dose of cediranib that's safe when used with chemotherapy drugs which stop tumor growth by killing cells or stopping their division/spread.

Participant Groups

Group I: Arm I (pemetrexed disodium, cisplatin, cediranib maleate)) Experimental Treatment 4 Interventions

Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (pemetrexed disodium, cisplatin, placebo) Active Control 4 Interventions

Patients receive pemetrexed disodium and cisplatin as in arm I and placebo PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive placebo alone PO QD in the absence of disease progression or unacceptable toxicity.

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union 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 United States 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 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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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]

In a study of 49 patients with malignant pleural mesothelioma, the combination of carboplatin and pemetrexed achieved a disease control rate of 69% and a median overall survival of 14 months, indicating its effectiveness as a treatment option.

The treatment was generally well-tolerated, with only 14.3% of patients experiencing severe haematological toxicities and 24.5% experiencing severe non-haematological toxicities, and no toxic deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and pemetrexed in the management of malignant pleural mesothelioma: a realistic treatment option? Li, L., Razak, AR., Hughes, A.[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 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]

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]

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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

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

2. Australia pubmed.ncbi.nlm.nih.gov

Audit of patients with mesothelioma treated with pemetrexed in a single institution in Western Australia. [2015]

3. Italy pubmed.ncbi.nlm.nih.gov

Advanced epithelioid pleural mesothelioma, long lasting disease stabilization and long term survival with cisplatin-pemetrexed chemotherapy re-challenge: a case report. [2020]

4. Japan pubmed.ncbi.nlm.nih.gov

Retreatment of recurrent malignant pleural mesothelioma with cisplatin and pemetrexed. [2018]

5. Ireland pubmed.ncbi.nlm.nih.gov

Outcomes with first-line platinum-based combination chemotherapy for malignant pleural mesothelioma: a review of practice in British Columbia. [2022]

6. 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]

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

Carboplatin and pemetrexed in the management of malignant pleural mesothelioma: a realistic treatment option? [2015]

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

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

9. 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]

10. 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]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients. [2022]

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

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