J Clin Oncol 24: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 24 NUMBER 19 JULY JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Progression-Free Survival Rate As Primary End Point for Phase II Cancer Clinical Trials: Application to Mesothelioma The EORTC Lung Cancer Group Julie Francart, Catherine Legrand, Richard Sylvester, Martine Van Glabbeke, Jan P. van Meerbeeck, and Annie Robert From the European Organisation for Research and Treatment of Cancer; Université Catholique de Louvain, Brussels; and University Hospital, Ghent, Belgium. Submitted December 8, 2005; accepted April 11, Supported by a grant from the Fédération Belge contre le Cancer, Brussels, Belgium and by Grants No. 5U10 CA and 5U10 CA from the National Cancer Institute, Bethesda, MD. Presented in part at the 5th International Meeting of French Society of Statistics (SFdS) Statistical Innovations in Clinical Trials, Paris, France, September 26-27, The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Address reprint requests to Julie Francart, MSc, Université Catholique de Louvain, Unité EPID 3034, Clos Chapelle-aux-champs, 30, BE-1200 Brussels, Belgium; julie.francart@epid.ucl.ac.be by American Society of Clinical Oncology X/06/ /$20.00 DOI: /JCO A B S T R A C T Purpose Phase II cancer clinical trials play a key role in the development of new drugs. These trials should be designed to accurately determine if the drug should be abandoned or if it is sufficiently promising for further investigation in phase III trials. With new cytostatic agents or when the response assessment is difficult, using the progression-free survival rate (PFSR) at a fixed time point, such as 3, 4, 5, or 6 months, instead of the response rate (RR) as the primary end point is an alternative approach. To design future phase II trials, reference values for PFSRs that correspond to drugs with insufficient (P0) and sufficient (P1) clinical activity (CA) are necessary. This article provides these values in mesothelioma. Materials and Methods The European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients. Trials were grouped into three categories according to the published RR: significant (n 259), moderate (n 142), and insufficient (n 122) CA. Results The PFSRs at 3, 4, 5, and 6 months, respectively, were as follows: 72%, 67%, 51%, and 43% in the group with significant CA; 59%, 51%, 42%, and 35% with moderate CA; and 52%, 40%, 34%, and 28% with insufficient CA. Conclusion These values may be used to define relevant P0 and P1 values in future phase II mesothelioma trials that use PFSR as the primary end point. J Clin Oncol 24: by American Society of Clinical Oncology INTRODUCTION The aim of phase II cancer clinical trials is to screen new drugs for their biologic antitumor activity. Phase II trial designs were originally developed for the investigation of cytotoxic drugs, to assess activity by measuring the degree of shrinkage of target lesions. The most appropriate end point to document biologic activity is the response to therapy based on determining the decrease in the size of target lesions. However, this end point may not be appropriate in several situations, such as when the response is difficult to evaluate or the agents studied are noncytotoxic (cytostatic), because their biologic activity is characterized by the stabilization of the disease rather than the shrinkage of lesions. These agents slow or stop the growth of tumors and the development of metastases. Thus, other more appropriate end points must be considered. 1 Using the progression-free survival rate (PFSR) at a fixed time point (eg, 3, 4, 5, or 6 months), instead of the response rate (RR) as the primary end point, is one proposed method. 2 In classical phase II designs, the sample size is computed on the basis of two rates of success: P0 and P1. P0 is the rate of success below which the drug is considered inactive (insufficient activity). P1 is the rate of success above which the drug is considered active (sufficient activity). These reference rates will obviously differ if the definition of success is changed from response (related to decreased size of the lesion) to the patient s PFSR at a fixed point in time. In order to design future phase II trials using the PFSR as the primary end point, P0 and P1 for the PFSR must be known. Published data for RRs are widely available. In contrast, there are few published data about the PFSR at 3, 4, 5, or 6 months. When available, they often measure the PFSR at one year or greater. 3007

2 Francart et al Table 1. Therapeutic Regimen Trials Patients Regimen Treatment Schedule Phase II Mitoxantrone 14 mg/m 2, 30-min infusion, q 3 weeks epidoxorubicin 110 mg/m 2, 3 weekly Etoposide 150 mg/m 2, IV days 1, 3, 5, q 3 weeks Etoposide 100 mg, PO days 1-21, q 5 weeks Paclitaxel 200 mg/m 2, 3-hour infusion, q 3 weeks Gemcitabine 1,250 mg/m 2, 30-min infusion, days 1, 8, 15, 28, q 4 weeks Pegylated liposomal doxorubicin 45 mg/m 2, 1-day infusion, q 4 weeks Temozolomide 200 mg/m 2 /d, PO days 1, 2, 3, 4, 5, q 4 weeks Raltitrexed 3 mg/m 2, 15-min infusion, q 3 weeks Phase III Cisplatin alone 80 mg/m 2, 1 day 1-2 hour infusion, q 3 weeks Raltitrexed with cisplatin Tomudex 3 mg/m 2, 1 day 15 min infusion followed by cisplatin 1 day 1-2 hour infusion, q 3 weeks Abbreviations: q, every; IV, intravenously; PO, by mouth. As the incidence of mesothelioma increases and the median survival remains is only between 9 and 13 months, 3 the development of new, more active drugs is needed. New cytostatic agents should be investigated to determine their potential activity. In addition, the tumor volume in mesothelioma is difficult to accurately assess, so RRs are often not reproducible. 3 Thus, the PFSR at a fixed time point is of interest in assessing new drug activity in mesothelioma. This article will provide appropriate reference values of P0 and P1 when using the PFSR at 3, 4, 5, or 6 months for designing phase II trials in mesothelioma. MATERIALS AND METHODS Between October 1984 and June 2001, the European Organisation for Research and Treatment of Cancer Lung Cancer Group conducted a large phase II program, screening the activity of several different single agents in the first-line treatment of mesothelioma. Nine phase II trials were included in this program. After that, one phase III trial that closed in January 2003 was implemented to test a combination of two drugs. Further details on the regimens used in these 10 trials are listed in Table In all these trials, a histologically or cytologically proven diagnosis of malignant mesothelioma, at any stage, was required. Patients were chemotherapynaïve. No prior radiotherapy was allowed except palliative radiotherapy, and prior surgery was permitted only if there was evidence of disease recurrence thereafter. The presence of symptoms of CNS metastases was an exclusion criteria. Patients were aged from 18 to 80 years and had WHO performance status (PS) levels 2. The hematologic and biologic inclusion criteria were similar among the trials (Table 2). Response to therapy was evaluated according to WHO criteria in all trials except the two most recent trials, 4,5 which used Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria. WHO criteria are based on the sum of products of the two longest perpendicular diameters, 13 whereas RECIST criteria use the sum of the longest unidimensional diameters. 14 According to WHO criteria, disease progression was defined as a 25% or greater increase in the size of at least one measurable or assessable lesion or as the appearance of a new lesion. According to RECIST criteria, progression was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started or since the appearance of at least one new lesion. Assessments of response were repeated every 6 to 15 weeks, according to the trial. In all trials, patients were observed at least until progression. Table 2. Hematologic and Biologic Inclusion Criteria Trials Hemoglobin, g/l WBCs, 10 9 /L Platelets, 10 9 /L Bilirubin, mol/l ULN Albumin, g/dl 3 3 Creatinine, mol/l Creatinine clearance, ml/min ALT or AST, ULN Abbreviation: ULN, upper limit of normal. Calculated according to Cockroft-Gault s formula. 3, if liver 3008 JOURNAL OF CLINICAL ONCOLOGY

3 Progression-Free Survival for Mesothelioma Trials Based on the published results of RRs, trials were categorized into three groups: significant clinical activity (SCA), moderate clinical activity (MCA), and insufficient clinical activity (ICA). The first group corresponded to the phase III trial arm treated with raltitrexed and cisplatin. The second group included the phase III trial arm treated with cisplatin alone and the trial arm treated with raltitrexed alone. The other phase II trials, all testing a single agent, were included in the third group. In these three groups, the PFSR was calculated from the start of treatment until the date of progression or death from any cause. The PFSRs at 3, 4, 5, and 6 months were estimated by the Kaplan-Meier method. These rates estimated the proportion of patients who did not progress and were alive at a given time. The 95% confidence intervals for the PFSRs were estimated using Greenwood s estimate of the standard error (SE) and a linear transformation of the progression-free survival function. Statistical Analysis Software (SAS) Version 9.1 was used for data analysis. RESULTS Seventy-five of the 598 patients registered in the ten trials were excluded: 41 because of ineligibility; nine because of incoherent or missing data; and 25 because they did not have a definite or probable histologically proven diagnosis. Therefore, 523 total patients were included in this analysis, with 122, 142, and 259 patients in the SCA, MCA, and ICA groups, respectively. Patient and tumor characteristics are summarized in Table 3. Patients were predominantly male and had a PS of 0 or 1. The median age was 58 years (range, 19 to 80 years). In most cases, the diagnosis was histologically proven (85%), and the most frequent histologic subtype was epithelial (59%). Twenty-three percent of patients had stage I or II disease, 39% had stage III disease, and 26% had Characteristic Table 3. Baseline Characteristics Clinical Activity Significant Moderate Insufficient Total patients Age, years Median Range Sex Male Female Performance status (WHO scale) Histologically proven diagnosis Definite Probable Trial (definite and probable) Histologic subtype Epithelial Sarcomatous Mixed Missing Stage of disease (IMIG staging system) 15 Stage I and II Stage III Stage IV Missing Time interval since first diagnosis, days Median Range 5, 1,799 4, 1,485 2, 5,500 2, 5,500 WBC, 10 9 /L Median Range 4.3, , , , 18.3 Platelets, 10 9 /L Median Range 153, , , , 968 Hemoglobin, g/l Median Range 101, , , , 196 * In the three oldest trials, data were recorded in Butchart s staging system 16 and were converted to the IMIG staging system: Butchart I IMIG stages I and II, Butchart II IMIG any T3 or N2. Butchart III IMIG any T4 or N3, Butchart IV IMIG. In trial (n 41), these data were missing

4 Francart et al Table 4. Response, Follow-Up, Overall Survival, and Progression-Free Survival Clinical Activity Significant Moderate Insufficient patients Response rate, % % CI for response rate 14 to 29 8 to 19 4 to 10 9 to 14 Median follow-up, months Overall survival deaths Median, months % CI for median 9.5 to to to to 10.2 Progression-free survival progressions or deaths Median, months % CI for median 4.5 to to to to 4.3 Total stage IV disease. The median WBC count, platelet count, and hemoglobin were /L, /L, and 127 g/l, respectively. Baseline characteristics, except for disease stage, were similar in the three groups. Table 4 reports the RRs, median durations of follow-up, progression-free survival, and overall survival data for the SCA, MCA, and ICA groups. The RRs of each group were 21%, 13%, and 6%, respectively. Five hundred six (97%) of the 523 patients progressed or died during follow-up. The median survival and the median progression-free survival rates were 11.4 and 5.3, 8.8 and 4.0, and 8.6 and 3.2 months, in the three groups, respectively. The PFS curves of the different groups are shown in Figure 1. The Kaplan- Meier estimates of PFSR at 3, 4, 5, and 6 months are reported in Table 5. The PFSRs decreased across the three groups and the four time points. In the SCA group, the PFSR decreased from 72% at 3 months to 43% at 6 months, and these values were higher than those observed in the two other groups. DISCUSSION As the incidence of malignant mesothelioma has increased in the last 20 years, optimizing treatment, controlling symptoms, and prolonging life have become more important. The median survival of patients with mesothelioma is between 9 and 13 months, and survival has not been significantly affected by most currently available therapeutic interventions. 3,17 In view of the short life expectancy and the insufficient results of current treatments, the development of new, more active regimens is needed in the management of malignant mesothelioma. Phase II clinical trials play an important part of the drugdevelopment process, because the molecule may be definitively abandoned if it does not show sufficient therapeutic promise. The statistical design may influence the success or failure of a treatment in a phase II trial, so it is important to adapt the statistical design of a phase II trial to the treatment and the disease. Currently, there is a large development of new cytostatic drugs, which are characterized by the stabilization of disease rather than by the shrinkage of lesions. Therefore, using standard cytotoxic trial designs based on the RR may lead to rejection of a clinically useful cytostatic agent. 2 In addition, the difficulty of response assessment in mesothelioma has to be taken into account in the design. Pleural mesothelioma typically shows a parietal growth pattern, and often no circumscribed tumor mass can be delineated radiographically. This makes response evaluation in mesothelioma patients Table 5. Progression-Free Survival Rates at 3, 4, 5, and 6 Months At 3 Months At 4 Months At 5 Months At 6 Months Fig 1. Progression-free survival curves according to clinical activity. O, observed events; N, number of patients; SCA, significant clinical activity; MCA, moderate clinical activity; ICA, insufficient clinical activity. Significant CA Rate, % % CI 64 to to to to 51 Moderate CA Rate, % % CI 50 to to to to 43 Insufficient CA Rate, % % CI 46 to to to to 34 Abbreviation: CA, clinical activity JOURNAL OF CLINICAL ONCOLOGY

5 Progression-Free Survival for Mesothelioma Trials notoriously difficult. 3,18 A clinical end point that may be affected by a cytostatic agent and more easily evaluated would be of interest in mesothelioma. Such an end point is the PFSR at a fixed time point. Replacement of the RR by the PFSR at a fixed time point as the primary end point in future mesothelioma phase II trials would allow a better selection of clinically active drugs for phase III trials. Using the PFSR as the primary end point in future phase II trials requires that P0 and P1, the two rates of success for designing a phase II trial, be known for the PFSR rather than the RR. Our results provide the PFSRs at 3, 4, 5, and 6 months, which may be used as reference values for P0 and P1 in the design of future phase II mesothelioma trials. The choice of reference values should account for the disease and its natural course, which may be slowly progressive. Indeed, when the disease progresses slowly, the PFSR at greater than 6 months may be used in order to distinguish the treatment effect from the natural history. The PFSR at an earlier time point (eg, 3, 4, or 5 months) may be used when the disease progresses more rapidly. Mesothelioma, with a median survival of 9 to 13 months from diagnosis, 3 is a rapidly progressing disease; thus, the PFSR at 3, 4, 5, or even 6 months is appropriate. According to the stage of disease, PFSR at 3 or 4 months may be preferred for advanced stages, and PFSR at 5 or 6 months may be used for more localized disease. The choice of reference values also should be made according to the treatment type (single agent or combination). In future phase II trials using a single agent, the choice of P0 and P1 may be based on values in the ICA and MCA groups, respectively, whereas, in trials with a combination of drugs, the choice of P0 and P1 may be based on values in the MCA and SCA groups, respectively. The actual P0 and P1 values should be consistent with the estimates and confidence intervals provided in Table 5. For example, instead of setting P1 equal to 72% at 3 months, 70% or 75% may be used, depending on factors such as drug toxicity and patient selection criteria. Sample size depends on P0 and P1 values and would not necessarily be larger when considering PFRS at a fixed time point. Depending on the reference value used, the required sample size could be slightly increased, decreased, or unchanged. For instance, to design a phase II trial testing a new combination of two agents in mesothelioma using a one-stage Fleming design (.10,.05), the required sample size may be calculated based on the values of P0 and P1: 10% and 25% if using the RR (based on the literature); 50% and 67% if using the PFSR at 4 months (corresponding to the results in Table 5). Fifty-four patients would be required when using the RR, and 66 patients would be necessary with the PFSR; the minimum required number of successes would be nine and 39, respectively. Moreover, using the PFSR instead of RR as the primary end point does not necessarily require a longer follow-up time or additional disease assessments. The only additional assessment might be one corresponding to the chosen fixed time point of 3, 4, 5, or 6 months. The additional resources required by using the PFSR are not considerable when compared with the improved ability to identify clinically active new drugs with this approach. The data from 10 different trials were easily merged because of their similar designs and similar eligibility criteria. Assessment of progression was performed according to WHO criteria in eight trials and according to RECIST criteria in the two most recent trials (08992, ). However, the ICA group included only trials using WHO criteria, and the two other groups included trials using only the RECIST criteria. The agreement between the RECIST and WHO criteria was validated in a comparative study, but tumors of chest wall, such as mesothelioma, were not included. 14 Because mesothelioma most commonly grows along the pleural surface, a chest computed tomography scan may not identify a spherical lesion with bidimensionally measurable diameters. RECIST criteria are more suited to tumor assessment in mesothelioma, because they specify the use of unidimensional measurements. Several studies have clearly demonstrated a discrepancy between WHO and RECIST response evaluation in mesothelioma patients. Compared with WHO criteria, RECIST criteria more often missed disease progression and classified patients as having stable disease. 18,19 Therefore, the PFSR was higher with RECIST criteria. The major problem in applying RECIST criteria to mesothelioma is the determination of the longest unidimensional diameter of the target tumor mass, because the measurement may not be reproducible. The more recent, modified RECIST criteria are now the preferred criteria in mesothelioma. 20 They were developed to avoid difficult and ambiguous situations in response assessment by specifying that the measurement site has to be perpendicular to fixed structures, chest wall, and vertebral column. The use of these criteria does not greatly alter the RR but does increase the reproducibility of response assessment. 20 In conclusion, phase II cancer clinical trials play a key role in the development of new drugs. Phase II trials must be designed to accurately determine if a new drug is promising for further investigation in a phase III trial. For the new cytostatic agents characterized by the stabilization of the disease, or for cases in which the response assessment is difficult, the RR as primary end point may be inappropriate. Using PFSR at a fixed time point instead is a better approach. To design future phase II trials in malignant mesothelioma with the PFSR as the primary end point, reference values for P0 and P1 have been provided. They are determined by taking into account the natural course of the disease and the treatment type. The European Organisation for Research and Treatment of Cancer Lung Cancer Group is currently designing a new phase II trial in mesothelioma using this methodology. REFERENCES 1. Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: Are new approaches needed? J Clin Oncol 19: , Van Glabbeke M, Verweij J, Judson I, et al: Progression-free rate as the principal endpoint for phase II trials in soft-tissue sarcomas. 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6 Francart et al phase II study of the EORTC Lung Cancer Cooperative Group. Br J Cancer 74: , van Meerbeeck JP, Baas P, Debruyne C, et al: A phase II study of gemcitabine in patients with malignant pleural mesothelioma. Cancer 85: , Baas P, van Meerbeeck JP, Groen H, et al: Caelyx in malignant mesothelioma: A phase II EORTC study. Ann Oncol 11: , van Meerbeeck JP, Baas P, Debruyne C, et al: A phase II EORTC study of temozolomide in patients with malignant pleural mesothelioma. Eur J Cancer 38: , WHO handbook for Reporting of Cancer Treatment. Geneva, Switzerland: World Health Organisation; Offset Publication N Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92: , International Mesothelioma Interest Group: A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 108: , Butchart EG, Ashcroft T, Barnsley WC, et al: Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura: Experience with 29 patients. Thorax 31:15-24, Sterman DH, Albelda SM: Advances in the diagnosis, evaluation and management of malignant pleural mesothelioma. Respirology 10: , van Klaveren RJ, Aerts JGJV, de Bruin H, et al: Inadequacy of the RECIST criteria for response evaluation in patients with malignant pleural mesothelioma. Lung Cancer 43:63-69, Monetti F, Casanova S, Grasso A, et al: Inadequacy of the new RECIST in patients with malignant pleural mesothelioma: Report of four cases. Lung Cancer 43:71-74, Byrne MJ, Nowak AK: Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 15: , 2004 Authors Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions Conception and design: Julie Francart, Richard Sylvester, Martine Van Glabbeke Administrative support: Annie Robert Provision of study materials or patients: Jan P. van Meerbeeck Collection and assembly of data: Julie Francart, Catherine Legrand, Jan P. van Meerbeeck Data analysis and interpretation: Julie Francart, Catherine Legrand, Richard Sylvester, Annie Robert Manuscript writing: Julie Francart, Catherine Legrand, Richard Sylvester, Jan P. van Meerbeeck, Annie Robert Final approval of manuscript: Catherine Legrand, Richard Sylvester, Martine Van Glabbeke, Jan P. van Meerbeeck, Annie Robert 3012 JOURNAL OF CLINICAL ONCOLOGY