Pemetrexed + Cisplatin +/- Cediranib for Mesothelioma

Not currently recruiting at 263 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Proarrhythmic drugs

Disqualifiers: HIV, Pregnancy, Heart failure, others

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

Compensation: Varies

Number of Visits: 18

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment plan for individuals with malignant pleural mesothelioma, a cancer affecting the lung lining. Researchers aim to determine how well cediranib, an experimental drug, combined with two chemotherapy drugs, pemetrexed and cisplatin, can inhibit cancer cell growth and spread. Participants will receive either the drug combination or a placebo with the chemotherapy drugs to compare effects. This trial may suit those with this type of mesothelioma who have not yet undergone major treatments like chemotherapy and do not plan to have surgery. As a Phase 1/Phase 2 trial, the study focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining cediranib maleate with chemotherapy drugs like cisplatin and pemetrexed can present safety issues. In one study, two out of six patients experienced severe side effects at the tested dose. However, this combination has proven more effective than chemotherapy alone for some patients with advanced mesothelioma.

Cisplatin and pemetrexed are well-known chemotherapy drugs. They are generally well-tolerated but can cause side effects like nausea or fatigue. As this trial is in its early stages, researchers are still determining the safest dose and monitoring for any side effects.

Overall, while potential benefits exist, the combination treatment may cause some side effects. Trial participants will be closely monitored to manage any issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using cediranib in combination with pemetrexed and cisplatin for mesothelioma because it offers a fresh approach to tackling the disease. Unlike standard treatments that mainly focus on chemotherapy agents like pemetrexed and cisplatin alone, cediranib is a VEGF receptor tyrosine kinase inhibitor. This means it targets the blood vessels that supply the tumor, potentially cutting off its blood supply and starving it. This mechanism could enhance the effectiveness of traditional chemotherapy, offering hope for better outcomes.

What evidence suggests that this trial's treatments could be effective for mesothelioma?

Research shows that using pemetrexed disodium and cisplatin together can effectively stop tumor growth in mesothelioma by killing cancer cells or preventing their spread. In this trial, one group of participants will receive this combination with the addition of cediranib maleate. Studies have found that cediranib can further improve results by blocking the tumor's blood supply and essential enzymes for cell growth. Specifically, cediranib improved progression-free survival, meaning the cancer did not worsen for a longer time, when used with cisplatin. While cediranib alone has limited effects, combining it with other chemotherapy drugs appears promising for controlling the disease. Early findings from other studies indicate that patients experienced partial responses or stable disease, suggesting potential benefits in managing mesothelioma. ^{1 6 7 8 9}

Who Is on the Research Team?

Anne S Tsao

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/22831987/

Cediranib in patients with malignant mesothelioma Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00309946

Cediranib Maleate in Treating Patients With Malignant ... This phase II trial is studying how well cediranib maleate works in treating patients with malignant mesothelioma that cannot be removed by surgery.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1556086415322590

Phase II Study of Cediranib in Patients with Malignant ... Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31386610/

Phase II Trial of Cediranib in Combination With Cisplatin and ... The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1. 1 (hazard ...

5. ascopubs.org ascopubs.org/doi/abs/10.1200/jco.19.00269

Phase II Trial of Cediranib in Combination With Cisplatin ... The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S155608641730429X

Phase I Trial of Cediranib in Combination with Cisplatin ... In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00243074?id=%22NCT00243074%22OR%22NCT00309946%22&rank=2

AZD2171 in Treating Patients With Malignant Pleural ... Determine the objective confirmed, complete, and partial response rates in patients with unresectable malignant pleural mesothelioma treated with AZD2171.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10735007/

Efficacy and safety profile of combining antiangiogenic agents ... The combination of antiangiogenic agents with chemotherapy showed superior over chemotherapy alone in patients with advanced MPM.

9. aacrjournals.org aacrjournals.org/clincancerres/article/20/13/3603/78400/Phase-II-Study-of-Cediranib-in-Patients-with

Phase II Study of Cediranib in Patients with Advanced ... Importantly, no new safety concerns were identified during this study. The majority of both GIST and STS patients required a cediranib dose reduction or pause ...