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Phase II Study of Vinflunine in Malignant Pleural Mesothelioma

Denis C. Talbot, Jacques Margery, Gérard Dabouis, Graham Dark, Henry Taylor, Hélène Boussemart, Véronique Cadic, Marie-Claire Pinel, Alain Rivière, Liliane Ollivier, Pierre Ruffié

From the Churchill Hospital, Oxford; Newcastle General Hospital, Newcastle upon Tyne; Kent Oncology Centre, Kent, United Kingdom; Institut Gustave Roussy, Villejuif; Hôpital Laënnec, Saint Herblain; Institut de Recherche Pierre Fabre, Boulogne-Billancourt; CF Baclesse, Caen; and Institut Curie, Paris, France

Address reprint requests to Denis Talbot, PhD, FRCP, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Headington, Oxford, OX3 7LJ, United Kingdom; e-mail: denis.talbot{at}cancer.org.uk

	ABSTRACT

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Purpose Malignant pleural mesothelioma (MPM) is a disease of increasing incidence for which treatment options are limited. This study reports the clinical efficacy data for vinflunine, a novel microtubule inhibitor, in MPM.

Patients and Methods Patients with a histologically confirmed diagnosis of MPM were eligible for enrollment onto this multicenter phase II trial if they had not received prior chemotherapy or radiotherapy and had measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Vinflunine 320 mg/m² by 10-minute intravenous infusion was administered on day 1 of 21-day cycles. Modifications of dose and schedule were made according to National Cancer Institute Common Toxicity Criteria version 2.0. Efficacy was assessed by an external, independent radiologist. The one-sample multiple testing procedure of Fleming was applied at the predetermined recruitment stages of 20 and 40 assessable patients.

Results Sixty-seven patients were enrolled. Five patients were not assessable for tumor response. The response rate was 13.8% (95% CI, 6.5% to 24.7%). The median survival was 10.8 months (95% CI, 7.8 to 12.0 months). The most common adverse events were anemia, neutropenia, fatigue, constipation, and nausea. Of grade 3 and 4 toxicities, neutropenia and constipation were the most common (45% and 9% of patients, respectively).

Conclusion Vinflunine can be delivered with high-dose intensity in patients with MPM. The response rate and median survival are encouraging for a single agent. These data suggest that vinflunine should be further evaluated in the management of MPM.

	INTRODUCTION

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Malignant pleural mesothelioma (MPM) is a rare thoracic disease associated with a poor prognosis and characterized by progressive dyspnea, chest wall pain, and anorexia. Its natural history is that of progressive disease, resistance to treatment intervention, and short survival.¹ There is a strong association of the disease with prior asbestos exposure, but a long latency period means that patients often present with mesothelioma 30 to 40 years after exposure. Because the use of asbestos was common in the mid-20th century, the incidence of the disease is now increasing rapidly, owing to the latency of onset, and is predicted to reach a peak between the years 2015 and 2019.²

Treatment options for MPM are limited. The disease may infiltrate the chest wall at sites of previous invasive procedures such as thoracoscopy or pleural biopsy. Prophylactic local radiotherapy to these sites may reduce the risk of invasion through the chest wall. Pleurectomy, or extrapleural pneumonectomy, in conjunction with radiotherapy and systemic treatment may be an option for patients with good performance status, based on the results of phase II studies. The role of surgery is being investigated in a randomized controlled trial (the MARS trial) being conducted in the United Kingdom.³ A number of systemic treatments have been evaluated in MPM, although response rates are usually low and no survival advantage has been demonstrated. The most active single agents are the anthracyclines, platinum agents, and vinca alkaloids, for which response rates range from 14% to 24%.⁴

Combination chemotherapy, usually based on anthracyclines and platinum-based agents, has not resulted in significantly improved response rates. The first study to demonstrate a survival benefit of combination therapy versus single-agent treatment in MPM was a randomized phase III study comparing the combination of pemetrexed with cisplatin versus cisplatin alone, leading to a statistically significant difference in median duration of survival.⁵ The median duration of survival of patients treated with pemetrexed plus cisplatin was 12.1 versus 9.3 months during cisplatin monotherapy. Clearly, there is a clinical need to develop other active agents that may be effective as first- or second line treatments of this disease.

Vinflunine ditartrate is a novel microtubule inhibitor that has been modified by the introduction of two fluorine atoms at the C 20' position of the catharanthine component of the vinca alkaloid molecule. The fluorine atoms are essential for the high level of antitumor activity in experimental tumor models in vivo.⁶ Vinflunine accumulates intracellularly, after active transport uptake, blocking cells at the G2/M phase of the cell cycle and inducing apoptosis. Vinflunine has the capacity to inhibit tubulin assembly without any stabilizing effect on assembled microtubules at concentrations comparable to those of other vinca alkaloids.^7,8 Vinflunine has markedly superior tumor growth inhibition against 11 human tumor xenografts and the National Cancer Institute (NCI) panel of tumor cells.⁹ Resistance to vinflunine develops less readily than to vinorelbine in vitro and in vivo, which may have important clinical implications.¹⁰ In view of the preclinical evidence of excellent antitumor activity, safety profile in phase I studies,^11,12 and activity of vinca alkaloids in MPM, there was good rationale for evaluating the activity of vinflunine in MPM.

The primary objective of this phase II study was to assess the overall response rate of patients with MPM in the first-line setting. Secondary objectives were to determine progression-free survival, and overall survival.

	PATIENTS AND METHODS

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Patient Selection
Informed, consenting patients were included in the study if they had histologic and immunocytochemical confirmation of MPM and at least one previously nonirradiated lesion, measurable by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) assessment.¹³ Measurable disease was defined as diffuse pleural thickening of at least 5 mm, assessed in three different areas, with the sum of the measurements of at least 20 mm or, for nodular disease, lesions of at least 20 mm in diameter with conventional techniques or at least 10 mm in diameter using spiral CT assessment. Patients were required to be at least 18 years of age; have had no prior chemotherapy or immunotherapy within 30 days of study entry; and have a Karnofsky performance status of at least 80%, an expected life expectancy of at least 12 weeks, and acceptable hematologic indices (absolute neutrophil count 2.0 x 10⁹/L, platelets 100 x 10⁹/L, and hemoglobin 9.5 g/dL), liver function tests (bilirubin 1.5x upper limit of normal [ULN], transaminases 2.5x ULN, or 5x ULN in the case of liver metastases), renal function (creatinine < 1.5x ULN) and a normal ECG. Prophylactic local radiotherapy to biopsy and/or thoracoscopic sites was acceptable if performed at least 15 days before study drug administration.

Patients were excluded if they had undergone previous large-field radiotherapy or if they had malignant mesothelioma of the peritoneum, pleural effusion and/or bone lesions as the only tumor site involvement, superior vena caval obstruction, weight loss of at least 10% within 3 months of registration, brain or leptomeningeal metastases, a history of other malignancies (unless there was a disease-free interval of at least 5 years and in patients with a prior history of adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix). Pregnant or lactating women were not included in the study, nor were those patients with serious illnesses including uncontrolled infection, heart failure, ischemic heart disease, or poorly controlled hypertension.

Study Design and End Points
This study was an open-label, multicenter international, noncomparative phase II trial. The one-sample multiple testing procedure of Fleming for phase II clinical trials was employed.¹⁴ A minimum of 20 and maximum of 60 assessable patients were required depending on the number of responses observed after accrual of 20 and 40 assessable patients. A small excess in recruitment was planned to replace possible patient withdrawal or noncompliance. Efficacy was assessed in all treated study patients who received at least two cycles of vinflunine except in cases of early progression or early death resulting from progression. The response rate was determined using RECIST.¹³ Toxicity was recorded throughout the treatment period and before each administration of vinflunine according to the NCI Common Toxicity Criteria (CTC) version 2.0. Patients having received at least one cycle of vinflunine were considered assessable for safety analysis.

Treatment Plan
Vinflunine was administered over a 10-minute infusion through a fast-running infusion of normal saline at a dose of 320 mg/m² on day 1 of a 21-day cycle. Treatment was delayed 1 week if the absolute neutrophil count was below 1 x 10⁹/L and/or platelets were less than 100 x 10⁹/L on day 1 of any cycle. A dose reduction to 280 mg/m² was made for subsequent cycles if an episode of febrile neutropenia and/or grade 4 neutropenia lasting more than 7 days was observed. Major organ toxicity of greater than CTC grade 2 on day 1 of any cycle led to a planned 1-week treatment delay or discontinuation of treatment if toxicity of grade 2 persisted for more than 2 weeks. For patients with mucositis or constipation of grade 3 or grade 2 for more than 5 days, the protocol mandated a dose reduction to 280 mg/m² or, on subsequent episodes, to 250 mg/m².

Patients were to be treated until disease progression or unacceptable toxicity. Routine use of prophylactic colony-stimulating factors was not permitted.

Efficacy and Safety Assessment
Disease assessment was to be performed at baseline and repeated every 6 weeks. A clinical safety assessment was to be performed with each cycle of treatment, as were physical examination, hematologic and biochemical profiles, ECG, and other investigations as clinically indicated. Because the primary end point of the study was overall response rate, radiologic assessments were reviewed by an external, independent radiologist.

Statistical Methods
The statistical analysis was performed on all treated patients and the population assessable for response. The overall response of patients was defined as the best response confirmed from the date of registration until end of treatment. The objective response rate was defined as the number of patients with a complete or partial response expressed as a percentage of the patients enrolled and treated into the study. CIs of 95% were calculated using Fisher's exact method. The duration of response was determined by the Kaplan-Meier method for patients who achieved an objective response according to RECIST, from the time measurement criteria were met until the date of progression or death resulting from any cause. Patients lost to follow-up, or who reached the time point of analysis without a known record of progression or death, had the duration of response excluded at the date of last tumor assessment or last contact of a follow-up showing no progression, whichever occurred last. Patients who received a new antitumoral treatment before their disease progression were censored at the start date of this new antitumoral treatment. Progression-free survival was calculated from the registration date until the date of progression or death resulting from any cause. Patients lost to follow-up and those who reached the time point of analysis without a known record of progression or death had the progression-free survival excluded at the date of last tumor assessment or last contact of a follow-up showing no progression, whichever occurred last. Overall survival was defined as the time elapsed from registration date to date of death from any cause. Survival time was excluded at the date of last review. Progression-free survival and overall survival were calculated using the Kaplan-Meier method. Dose-intensity was presented by median, range, and as a percentage of the theoretical dose for all treated patients. Safety analysis was performed on all treated patients. Worst NCI-CTC grade was tabulated by cycle and by patient.

	RESULTS

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Between July 2002 and July 2004, 67 patients with MPM from nine centers were included in the study. Two patients included in the study were not treated: One patient withdrew his consent, and the other had a fall before the treatment, which resulted in a reduction in performance status. These patients are not included in the analysis. Three (4.6%) of the remaining 65 patients were not assessable for response (no target lesion [n = 1]; not eligible because of concomitant serious illness [n = 1]; and withdrawal after one cycle because of toxicity [n = 1]).

Table 1 reports the demographic details of patients entered onto the study, histologic subtypes, and stage distribution according to International Mesothelioma Interest Group (IMIG) classification. Approximately 70% of patients had advanced (stages III to IV) disease at initial diagnosis. Sites of metastatic disease (excluding pleura) were lung, four patients (6.2%); lung and liver, one patient (1.5%); lymph nodes, 20 patients (30.8%); soft tissue, seven patients (10.8%); skin, one patient (1.5%); and other, four patients (6.2%). The median time from diagnosis to study entry was 0.4 years (range, 0.04 to 7.20 years).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free survival, all treated patients. RECIST, Response Evaluation Criteria in Solid Tumors.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival, all treated patients.

Safety Evaluation
A total of 264 cycles were administered, with a median of four cycles per patient (range, 1 to 9 cycles). Ten cycles (3.8%) were administered at 280 mg/m², with all other cycles administered at full dose. Among second or subsequent cycles, 20 (10%) were delayed because of hematologic toxicity (n = 2), non–study-drug related adverse event (n = 3), and other reasons (n = 15). The relative dose intensity was 98.9% (range, 77% to 103%).

Table 3 summarizes all adverse events of grade 3 or 4 toxicity and adverse events that had an overall incidence (of any grade toxicity) of 20% or more. Of the 65 patients, the most frequently encountered adverse events were: anemia (74%), neutropenia (71%), fatigue (72%), constipation (66%), nausea (55%), stomatitis (49%), abdominal pain (40%), vomiting (35%), neuropathic pain (26%), myalgia (25%), sensory neuropathy (21%), and alopecia (46%). Grade 3 toxicities were mainly neutropenia (31%), leucopenia (20%), constipation (9%), and fatigue (5%). No grade 3/4 neuropathy occurred. Grade 4 adverse events were reported for neutropenia (14% of patients), leucopenia, cardiac ischemia, infection without neutropenia, chest pain, adult respiratory distress syndrome (ARDS), and dyspnea (1.5% each). Injection-site reactions were reported in 33 (21%) of 157 delivered treatments in peripheral veins and affected 19 of 44 patients. No grade 3 phlebitis was reported. There were no episodes of febrile neutropenia of any grade.

	DISCUSSION

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This phase II study was designed to test the activity and safety of vinflunine administered as first-line treatment to patients with MPM. The study demonstrated a tumor response rate of 13.8%, and all responses were reviewed and validated by an external and independent radiologist. The median progression-free survival was 3.2 months, and median overall survival was 10.8 months. These results suggest that vinflunine is among the most active single agents in MPM.

The demographic details of the 65 patients participating in the study are typical of the population of patients with MPM who would be considered for systemic treatment. The most common histologic subtype was epithelial mesothelioma, and the large majority of patients had advanced disease. Treatment was generally well tolerated, with a median number of four cycles per patient and a maximum of nine cycles administered. The median relative dose-intensity was 98.9%.

Many reported studies of systemic therapy in MPM have been small, nonrandomized phase II trials. Patients' characteristics are often different between studies in regard to stage and prognostic factors, making comparisons between studies difficult.⁴ The natural history of MPM is that of gradual infiltration around the pleura in a sheet-like fashion and by direct invasion of the chest wall. Metastatic disease is well recognized, but uncommon. This biologic behavior means that objective tumor response measurements are difficult radiologically. The RECIST criteria do not lend themselves well to application to MPM and need to be modified for a meaningful assessment of response in this disease.^15,16

Historically, anthracyclines and platinum analogs have been the most widely studied cytotoxic agents in MPM. Doxorubicin has a reported response rate of 14% and median survival of 7.3 months,¹⁷ and epirubicin and liposomal doxorubicin were associated with disappointing response rates.^18,19 Cisplatin, as a single agent, has a reported overall response rate of 14% at a dose of 100 mg/m².²⁰ Gemcitabine has limited activity as a single agent.²¹ Because the alpha-folate receptor gene is overexpressed in up to 72% of MPM tumors, antifolates, including methotrexate,²² ralitrexed, ²⁴and, more recently, the multitargeted antifolate pemetrexed, have been evaluated. The combination of pemetrexed and cisplatin is considered the current standard of care for the treatment of MPM on the basis of the results of a randomized phase III trial comparing the combination with single-agent cisplatin. The pemetrexed/cisplatin combination was more effective than cisplatin alone, in terms of survival (12.1 v 9.3 months).²⁴ The European Organisation for the Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada have reported the results of a phase III trial comparing single-agent cisplatin with combination cisplatin/raltitrexed.²⁵ Median survival for patients in the combination arm was 11.2 months compared with 8.8 months for single-agent cisplatin. However, this difference was not statistically significant. Other agents are currently under investigation, including histone deacetylase inhibitors, inhibitors of mTOR (mammalian target of rapamycin), proteasome inhibitors and combinations of inhibitors of the cell surface membrane growth factor receptor kinases epidermal growth factor receptor (EGFR) and vascular EGFR (VEGFR).

This trial has indicated that vinflunine is a safe drug for patients, is generally well tolerated, and can be delivered at high dose-intensity. The most frequently observed adverse effects include anemia, leucopenia, fatigue, and nausea. However, the NCI-CTC grade of toxicity is generally 1 to 2. Because injection site reactions, albeit grade 1 or 2, were seen in approximately 50% of patients, it is recommended that vinflunine be very carefully administered.

Studies of vinflunine in vitro have shown significant synergy with cisplatin.²⁶ Phase II studies of the combination of vinflunine with carboplatin and cisplatin have demonstrated antitumor activity in non–small-cell lung cancer.^27-30 A phase I trial combining vinflunine and pemetrexed in solid tumors is ongoing. The results of our study, in terms of response rate and survival, suggest that vinflunine should be further evaluated in MPM after progression with cisplatin/pemetrexed because no other therapy is available in this setting. Synergy with cisplatin in the clinical setting should also be explored in this disease.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Denis C. Talbot

Administrative support: Helene Boussemart, Veronique Cadic, Marie-Claire Pinel

Provision of study materials or patients: Denis C. Talbot, Jacques Margery, Gerard Dabouis, Graham Dark, Henry Taylor, Alain Riviere, Liliane Ollivier, Pierre Ruffie

Collection and assembly of data: Denis C. Talbot, Jacques Margery, Graham Dark, Henry Taylor, Helene Boussemart, Veronique Cadic, Marie-Claire Pinel, Alain Riviere, Liliane Ollivier, Pierre Ruffie

Data analysis and interpretation: Denis C. Talbot, Gerard Dabouis, Helene Boussemart, Veronique Cadic, Marie-Claire Pinel

Manuscript writing: Denis C. Talbot, Jacques Margery, Gerard Dabouis, Graham Dark, Henry Taylor, Helene Boussemart, Veronique Cadic, Marie-Claire Pinel, Alain Riviere, Liliane Ollivier, Pierre Ruffie

Final approval of manuscript: Denis C. Talbot, Marie-Claire Pinel

	NOTES

 
Supported by Cancer Research UK and Pierre Fabre Oncology.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted May 14, 2007; accepted July 9, 2007.

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