Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma (original) (raw)
Related papers
The Lancet, 2016
Background Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove eff ective. We aimed to assess the eff ect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as fi rst-line treatment of advanced malignant pleural mesothelioma. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural eff usion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-infl ammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0•8]; patients stratifi ed by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0-1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m² pemetrexed plus 75 mg/m² cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic eff ects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456. Findings From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was signifi cantly longer with PCB (median 18•8 months [95% CI 15•9-22•6]) than with PC (16•1 months [14•0-17•9]; hazard ratio 0•77 [0•62-0•95]; p=0•0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3-4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. Interpretation Addition of bevacizumab to pemetrexed plus cisplatin signifi cantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic eff ects, therefore it should be considered as a suitable treatment for the disease. Funding Intergroupe Francophone de Cancérologie Thoracique (IFCT).
Journal of Thoracic Oncology, 2006
on behalf of pemetrexed expanded access program investigators* Background: In a randomized phase III trial, pemetrexed plus cisplatin was associated with improved survival compared with cisplatin alone for patients with malignant pleural mesothelioma (MPM). However, there are limited data available on the efficacy of these and other chemotherapy regimens in patients who have received previous systemic chemotherapy. To gather additional efficacy and safety data of pemetrexed/cisplatin and pemetrexed alone in previously treated patients, we examined patients treated on the Eli Lilly and Company expanded access program (EAP). Patients and Methods: Patients with malignant mesothelioma were enrolled in this trial. Of 1056 patients receiving at least one dose of the study drug, 187 (17.7%) were previously treated patients with MPM. Patients were treated every 21 days with pemetrexed 500 mg/m 2 alone (n ϭ 91) or in combination with cisplatin 75 mg/m 2 (n ϭ 96) for a maximum of six cycles. All patients received folic acid and vitamin B12 supplementation and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all patients enrolled in the EAP. Results: Median age of the previously treated pleural mesothelioma subset was 66 years (range, 27-87 years). Based on 153 evaluable patients (a subset of the larger intent-to-treat population of 187), the overall response rate was 32.5% for pemetrexed and cisplatin and 5.5% for pemetrexed alone. The disease control rate (response rate ϩ stable disease) was 68.7% for pemetrexed and cisplatin and 46.6% for pemetrexed alone. Median survival was 7.6 months for pemetrexed plus cisplatin (67% censored) and 4.1 months for pemetrexed alone (55% censored). The most commonly reported serious adverse events in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). Conclusions: The data from this EAP study suggest that patients with previously treated MPM can benefit from treatment with pemetrexed alone or in combination with cisplatin. The treatment is associated with acceptable toxicity.
Journal of Clinical Oncology, 2004
on behalf of pemetrexed expanded access program investigators* Background: In a randomized phase III trial, pemetrexed plus cisplatin was associated with improved survival compared with cisplatin alone for patients with malignant pleural mesothelioma (MPM). However, there are limited data available on the efficacy of these and other chemotherapy regimens in patients who have received previous systemic chemotherapy. To gather additional efficacy and safety data of pemetrexed/cisplatin and pemetrexed alone in previously treated patients, we examined patients treated on the Eli Lilly and Company expanded access program (EAP). Patients and Methods: Patients with malignant mesothelioma were enrolled in this trial. Of 1056 patients receiving at least one dose of the study drug, 187 (17.7%) were previously treated patients with MPM. Patients were treated every 21 days with pemetrexed 500 mg/m 2 alone (n ϭ 91) or in combination with cisplatin 75 mg/m 2 (n ϭ 96) for a maximum of six cycles. All patients received folic acid and vitamin B12 supplementation and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all patients enrolled in the EAP. Results: Median age of the previously treated pleural mesothelioma subset was 66 years (range, 27-87 years). Based on 153 evaluable patients (a subset of the larger intent-to-treat population of 187), the overall response rate was 32.5% for pemetrexed and cisplatin and 5.5% for pemetrexed alone. The disease control rate (response rate ϩ stable disease) was 68.7% for pemetrexed and cisplatin and 46.6% for pemetrexed alone. Median survival was 7.6 months for pemetrexed plus cisplatin (67% censored) and 4.1 months for pemetrexed alone (55% censored). The most commonly reported serious adverse events in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). Conclusions: The data from this EAP study suggest that patients with previously treated MPM can benefit from treatment with pemetrexed alone or in combination with cisplatin. The treatment is associated with acceptable toxicity.
Japanese Journal of Clinical Oncology, 2008
Background: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. Methods: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0-1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 (Level 1), were studied in the dose-escalation Phase I (Step 1). The RD determined in Step 1 was carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18-38. Results: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level 21 (pemetrexed 500 mg/m 2 , cisplatin 60 mg/m 2 ). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3-61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. Conclusion: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world. Downloaded from *Not calculated. NA, not assessed. Level 1: pemetrexed 500 mg/m 2 þ cisplatin 75 mg/m 2 . Level 21: pemetrexed 500 mg/m 2 þ cisplatin 60 mg/m 2 . CI, confidence interval. Jpn J Clin Oncol 2008;38(5) 343 by guest on January 8, 2016 http://jjco.oxfordjournals.org/ Downloaded from Level 1: pemetrexed 500 mg/m 2 þ cisplatin 75 mg/m 2. M, months. QOL, quality of life.
Journal of Thoracic Oncology, 2008
Introduction: Pemetrexed has established efficacy, and is the backbone for chemotherapy in patients with malignant pleural mesothelioma (MPM). An International Expanded Access Program provided Ͼ3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed plus platinum analogs (cisplatin or carboplatin) in 13 countries. In this article, we report the safety and efficacy data of MPM patients who were treated with single-agent pemetrexed (n ϭ 812). Methods: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed (500 mg/m 2) once (day 1) every 21 days with standard premedication and vitamin supplementation. Investigator-determined response and survival data were recorded at the end of study participation. Myelosuppression data were also collected. Results: All 812 MPM patients (319 chemonaïve; 493 pretreated) received single-agent pemetrexed (Ն1 dose) and were evaluated for safety. A total of 643 patients (247 chemonaïve, 396 pretreated) were evaluated for efficacy. Of the chemonaïve patients evaluated for efficacy (n ϭ 247), the overall response rate was 10.5%, median time to progressive disease (TTPD) was 6.0 months, and median survival was 14.1 month. Of the pretreated patients evaluated for efficacy (n ϭ 396), the overall response rate was 12.1%, median TTPD was 4.9 months, and the median survival was not estimable due to high censoring. Common terminology criteria grade 3/4 hematologic toxicity was mild in both groups, with neutropenia (Ͻ18%) as the main toxicity. Conclusions: In the present expanded access program, singleagent pemetrexed demonstrated promising activity in MPM in both chemonaïve and pretreated patients, with TTPD of 6.0 and 4.9 months, respectively, 1-year survival Ն54.7%, and mild hematologic toxicity.
Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma
Cancer, 2008
BACKGROUND. We conducted a phase 2, multicenter, open-label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non-small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity.
The Lancet Respiratory Medicine, 2019
Background Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma. Methods This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged ≥18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intentionto-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100.
Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma
Journal of Clinical Oncology, 2006
Purpose This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM). Patients and Methods Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2 and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12 supplementation. Pemetrexed was provided within the Expanded Access Program. Results A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to prog...