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Japanese Journal of Clinical Oncology Advance Access originally published online on April 22, 2008
Japanese Journal of Clinical Oncology 2008 38(5):339-346; doi:10.1093/jjco/hyn024
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© The Author (2008). Published by Oxford University Press. All rights reserved

Efficacy and Safety of Pemetrexed in Combination with Cisplatin for Malignant Pleural Mesothelioma: A Phase I/II Study in Japanese Patients

Kazuhiko Nakagawa1, Koichi Yamazaki2, Hideo Kunitoh3, Toyoaki Hida4, Kenichi Gemba5, Tetsu Shinkai6, Yukito Ichinose7, Susumu Adachi8, Yoshihiro Nambu9, Nagahiro Saijo10 and Masahiro Fukuoka1

1 Kinki University School of Medicine, Department of Medical Oncology, Osakasayama, Osaka
2 Hokkaido University School of Medicine, First Department of Medicine, Sapporo
3 National Cancer Center Hospital, Department of Internal Medicine and Thoracic Oncology, Tokyo
4 Aichi Cancer Center Hospital, Department of Thoracic Oncology, Nagoya
5 Okayama Rosai Hospital, Department of Respiratory Medicine, Okayama
6 NHO Shikoku Cancer Center, Department of Medicine and Thoracic Oncology, Matsuyama
7 National Kyushu Cancer Center, Department of Thoracic Oncology, Fukuoka, Japan
8 Eli Lilly and company, Lilly Research Laboratories, Indianapolis, IN, USA
9 Eli Lilly Japan K.K., Lilly Research Laboratories Japan, Kobe
10 National Cancer Center Hospital East, Kashiwa, Chiba, Japan

For reprints and all correspondence: Kazuhiko Nakagawa, Kinki University School of Medicine, Medical Oncology, 377-2 Ohnohigashi, Osakasayama 589-8511, Japan. E-mail: nakagawa{at}med.kindai.ac.jp

Received October 3, 2007; accepted March 1, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 Funding
 References
 
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/m2 and cisplatin 75 mg/m2 (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 –1 (pemetrexed 500 mg/m2, cisplatin 60 mg/m2). 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.

Key Words: cisplatin • mesothelioma • pemetrexed • phase I/II


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 Funding
 References
 
Malignant pleural mesothelioma (MPM) is a tumor derived from the mesothelium covering the surface of pleural membranes or from undifferentiated mesenchymal cells in connective tissue under the membranes. MPM is a locally invasive and aggressive tumor with a poor prognosis and a median survival time (MST) of {approx}9–16 months (1).

MPM is known to be linked to asbestos exposure, and the incidence of this tumor is expected to increase in the next 10–20 years according to an estimation of asbestos consumption in the world (9). Recently, the prevalence of MPM in Japan was widely recognized after uncovering the high incidence of MPM and MPM-related deaths in ex-workers of asbestos factories and in residents of the surrounding areas who may have been subject to non-occupational exposure to asbestos fibers.

Surgical resection offers local control of the tumor but its effect on survival remains unclear. In addition, application of radiation therapy is limited because of the diffuse extension of tumor spread. Regimens applied to lung cancer such as platinum-containing chemotherapy have been used for MPM in Japan; however, the efficacy outcomes of these therapies are not satisfactory. Therefore, effective systemic chemotherapy for MPM is clearly needed.

Pemetrexed is a novel antifolate (12) that inhibits three enzymes in folate metabolism: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase (11). Because of the multi-targeted profile of this compound, broad and preferable anti-tumor activity is expected. Pemetrexed has shown clinical activity in various tumors including mesotheliomas (6). A pivotal multicenter, randomized Phase III study of pemetrexed (500 mg/m2) in combination with cisplatin (75 mg/m2) versus cisplatin alone (cisplatin 75 mg/m2) in patients with MPM who had no prior chemotherapy was conducted in 20 countries (not including Japan) (16). A total of 448 patients were randomized and treated in this study (226 treated by pemetrexed/cisplatin (Pem/Cis) and 222 treated by cisplatin). MST in the Pem/Cis arm was 12.1 months compared with 9.3 months in the cisplatin arm (P = 0.020, two-sided log rank test). This was the first confirmation of significant prolongation of survival for patients with MPM. On the basis of this evidence, the combination of pemetrexed and cisplatin was approved for the treatment of MPM in the USA in 2004. Since then, the combination therapy has been approved in more than 80 countries and regions for the treatment of MPM, and recognized as a standard care for MPM (8).

In 2005, we initiated a Phase I/II study of Pem/Cis therapy in Japanese patients with MPM who had no prior chemotherapy. The primary objectives of this study were to determine the clinically recommended dose (RD) of Pem/Cis therapy in the Phase I portion of the study (Step 1), and to examine tumor response of the combination therapy in the Phase II portion (Step 2). The secondary objectives included time-to-event efficacy outcomes [the duration of response, progression free survival (PFS), and overall survival time], 1-year survival rate, quality of life (QOL) assessments, pulmonary function tests and safety.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 Funding
 References
 
Patient selection
Chemonaive patients with histological diagnosis of MPM, regardless of clinical stage and who were not candidates for curative surgery, were assessed for eligibility. Eligible patients needed to be 20–74 years old with a life expectancy ≥12 weeks and an Eastern Cooperative Oncology Group performance status (PS) 0 or 1. Patients were also required to have adequate organ functions: bone marrow reserve [platelets ≥100 x 103/mm3, hemoglobin ≥9.0 g/dl, and absolute neutrophil count (ANC) ≥2.0 x 103/mm3], hepatic function [bilirubin ≤1.5 x upper limit of normal (ULN), aspartate/alanine transaminase (AST/ALT) ≤2.5 x ULN, and serum albumin ≥2.5 g/dl], renal function (serum creatinine ≤ULN, and calculated creatinine clearance ≥45 ml/min using the Cockcroft and Gault formula), lung function (functional oxygen saturation [SpO2] ≥92%) and normal electrocardiogram.

Patients were excluded from this study for active infection, symptomatic brain metastasis, a wide-spread diffuse shadow in the lung caused by interstitial pneumonitis diagnosed by chest X-ray, pregnancy, serious concomitant systemic disorders incompatible with the study, clinically significant effusions, Common Terminology Criteria for Adverse Events (CTCAEs) v3 grade ≥2 peripheral neuropathy, the inability to discontinue aspirin and other non-steroidal anti-inflammatory agents or the inability or unwillingness to take folate and vitamin B12 during the study.

This study was conducted in compliance with the guidelines of good clinical practice and the Declaration of Helsinki, and it was approved by the local institutional review boards. All patients gave written informed consent before study entry. The Efficacy and Safety Evaluation Committee (ESEC), an independent body, was consulted if any efficacy and safety issues arose in the study.

Study Design
This was a Phase I/II, multicenter, single-arm, open-label study, performed in two steps. The RD level established in Step 1 was carried forward in Step 2. Patients enrolled in Step 1 at the RD level could continue in Step 2 unless otherwise indicated. The planned number of patients in total of Steps 1 and 2 treated with Pem/Cis was 18–38 for examination of efficacy and safety profile. In Step 1, six patients were to be enrolled in each dose level. The lower number of the planned number of patients, 18, was set as the minimum number of patients needed to confirm that the response rate of the study drugs was significantly larger than the threshold rate of 10% at one-sided significant level 0.05 with ≥80% power.

Study Treatment
Pemetrexed was intravenously administered as a 10-min infusion on Day 1 of a 21-day cycle, followed by cisplatin administration intravenously as a 2-h infusion 30 min after pemetrexed administration. Patients were instructed to take a daily 1 g multivitamin containing 500 µg of folate beginning 1 week prior to Day 1 of Cycle 1 until study discontinuation. Vitamin B12 (1000 µg) was intramuscularly injected, starting 1 week prior to Day 1 of Cycle 1 and repeated every 9 weeks until study discontinuation. Patients remained on study unless they were discontinued, for instance, due to disease progression and unacceptable adverse events.

Determination of RD for Step 2
In Step 1 (Phase I), four escalating dose levels were planned: pemetrexed at 500 (Level 1), 700 (Level 2), 900 (Level 3) and 1000 mg/m2 (Level 4) with cisplatin held at 75 mg/m2. In addition, a lower dose level (Level –1) was planned at pemetrexed 500 mg/m2 and a lower dose of cisplatin 60 mg/m2 for a failure case of dose-escalation in Level 1. In the dose-escalation procedure, the starting dose of pemetrexed was set to be 500 mg/m2 which is ca. 40% of the maximum tolerated dose (MTD) of pemetrexed monotherapy with folic acid and vitamin B12 supplementation determined in a Japanese Phase I study; the MTD and RD of pemetrexed were determined to be 1200 and 1000 mg/m2, respectively (7). The percentage of the starting dose to the MTD was based on a guideline for Phase I/II study on anticancer drugs (10). For escalation of pemetrexed dose, a modified Fibonacci dose-escalation method was used (2). Dose level reduction or escalation depended on the incidence of dose-limiting toxicity (DLT) at a given dose level (Fig. 1). If two of six patients at Levels 1, 2 or 3 developed DLT, that dose level was considered the RD for Step 2 (Phase II) of the study, and then Step 2 was initiated. This was also the case for Level –1 or 4 if 0–2 patients developed DLT. If three or more patients developed DLT at a given dose level (except dose Level –1), the next lower dose level was considered the RD level for Step 2. If three or more patients had DLT at Level –1, a decision was made as to whether the study should be continued.


Figure 1
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  		Figure 1. Scheme of dose-escalation Steps 1 and 2. DLT, dose-limiting toxicity.

 
A DLT was defined as a toxicity occurring in Cycle 1 meeting one of the following criteria: any grade ≥3 non-hematologic toxicity (except nausea, vomiting, anorexia and fatigue), grade ≥2 peripheral neuropathy or hearing loss/impairment, grade ≥3 febrile neutropenia (<1000/mm3 with ≥38.5°C), grade 4 leukopenia (<1000/mm3) or neutropenia (<500/mm3) lasting ≥3 days, thrombocytopenia (<25000/mm3), or thrombocytopenia requiring platelet transfusion. A failure to start the second cycle by Day 29 due to toxicity was also considered a DLT. All toxicities were assessed according to CTCAE.

Treatment Assessments
Anti-tumor Activity
Disease staging was assessed according to International Mesothelioma Interesting Group Tumor Node Metastasis (IMIG TNM) staging criteria (13). Within 28 days before the first treatment and approximately every 4 weeks after the first treatment, computer tomography or X-ray imaging of each lesion was performed. Tumor response was assessed using the modified Southwest Oncology Group (SWOG) criteria. Unidimensionally measurable lesions were defined as Measurable disease, and assessed objectively by the sum of the greatest diameters of them. Bidimensionally measurable lesions defined in the standard SWOG criteria (5) were assessed in the similar way. Best overall response selected from total overall response assessments was determined according to assessment of the Extramural Case Judgment Committee (E-CJC). Duration of response was measured as from the date of the first objective assessment of complete response (CR) or partial response (PR) until the date of the first assessment of progression of disease (PD). PFS was measured as from the registration date of Cycle 1 treatment until the first date of PD or death from any cause. Overall survival time was measured as from the registration date of Cycle 1 treatment until the date of death from any cause or until the last follow-up date in survival surveillance period.

QOL Assessments and Pulmonary Function Tests
QOL surveillance was employed using the following questionnaires: QOL questionnaire for cancer patients treated with anticancer drugs (QOL-ACD), and functional assessment of cancer therapy for lung cancer (FACT-L). These questionnaires were used on Day 1 of Cycles 1 and 2, and on 3 months after Day 1 of Cycle 1. QOL-ACD consists of four subscales (activity, physical condition, psychological condition and social relationships) and a total QOL scale (face scale) (4). The lung cancer subscale (LCS) score of FACT-L was used (3). As pulmonary function tests, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and vital capacity (VC) were measured using a spirometer in the sitting position. All tests followed the Japanese Respiratory Function Test guidelines (14).

Safety
Adverse events were recorded throughout the study and after the last drug administration until signs of recovery were evident. Adverse events were evaluated according to treatment-emergent adverse events (TEAEs) definitions, and coded using the Medical Dictionary for Regulatory Activities (MedDRA v9.0). The severity (grade) of an adverse event was assessed according to CTCAE v3.

Statistical Analysis
The evaluation period of efficacy and safety in this study was defined as from the beginning of the study treatment to 5 months after the last patient began study treatment. For the evaluations of overall survival time and 1-year survival rate, survival surveillance period was defined as from the beginning of the study treatment to 1 year after the last patient began study treatment. Patients who received the study drugs and complied with all inclusion/exclusion criteria were included in full analysis set (FAS). Patients who were treated with the RD level in Step 1 or 2 among FAS were included in efficacy analysis set for efficacy evaluation. Patients who received the study drugs at least once were included in safety analysis set for safety evaluation.

Assessment results of the best overall response by the E-CJC were used for efficacy analysis. Statistical tests based on binominal distribution were done to confirm that the response rate of the study drugs was significantly larger than the threshold rate of 10% at one-sided significant level 0.05. The threshold rate 10% was set on the basis of historical data on the response rate of cisplatin alone arm reported in other studies (15,16).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 Funding
 References
 
Patient Characteristics
From 2005 to 2006, a total of 25 Japanese patients with MPM were enrolled in Steps 1 and 2 at seven centers in Japan. All patients met the eligibility criteria and received study treatment; all were included in FAS. One patient was still receiving the study drug at the time of the efficacy and safety evaluations in this report.

Patient characteristics are summarized in Table 1. The majority of patients were male (22 patients, 88.0%). The median age was 61 years (range: 50–74 years). Most patients had a PS of 1 (18 patients, 72.0%) and clinical stage IV (21 patients, 84.0%). The predominant histologic subtype was epithelial in 64% of patients. Two demographic characteristics showed differences among dose levels. There were more patients with PS 0 in Level –1 (50.0%) than in Level 1 (21.1%). All six (100%) patients in Level –1 had the epithelial subtype versus 10 (52.6%) patients in Level 1.


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  		Table 1. Patient characteristics

 
Dose-Escalation, Dose-Limiting Toxicity and RD
One patient in Level 1 of Step 1 died on Day 14 of Cycle 1 due to exacerbation of pneumonia, respiratory failure (hypoxia) and disseminated intravascular coagulation (DIC). The ESEC evaluated the case of the early death. Since the patient had had the shadow of the lung detected by radiographic image prior to receiving study treatment, it was unlikely that the administration of pemetrexed was the primary cause of the pneumonia. The autopsy of this patient showed that interstitial changes in the lung were mild and the pathological diagnosis was an organizing pneumonia. The result of the autopsy was compatible with the clinical course and suggested that the direct cause of the death was not the drug-induced interstitial pneumonia but the exacerbation of infectious pneumonia, worsened by the study treatment. The case, therefore, was considered not appropriate for the DLT evaluation.

One patient was added in this dose level to assess the safety profile additionally. Among the six patients in Level 1 excluding the case inappropriate for the DLT evaluation, two patients showed DLTs: drug-induced pneumonitis in one patient and dose delay of Cycle 2 initiation due to decreased neutrophil count in the other. According to the protocol definition, Level 1 was determined to be an RD for the next phase (Fig. 1).

The ESEC, however, recommended examining the treatment at Level –1 (pemetrexed 500 mg/m2 and cisplatin 60 mg/m2) exploratively to accumulate more safety information. Accordingly, six patients were enrolled and treated at Level –1, and no DLTs were observed in this dose level.

Evaluating the data of these two levels together, the ESEC agreed to continue Step 2 carefully with the dose of Level 1. The sponsor decided to carry forward into Step 2 with an RD of Level 1 (pemetrexed 500 mg/m2 and cisplatin 75 mg/m2). In Step 2, 12 patients were treated at Level 1.

Efficacy
Nineteen patients (7 in Step 1 and 12 in Step 2) in Level 1 were included in the efficacy analysis set and of 19 patients, seven patients had PR, five patients had stable disease (SD), six patients had PD and one patient was classified as not evaluated. An overall response rate (ORR) was 36.8% [95% confidence interval (CI): 16.3%–61.6%]. The 95% one-sided confidence lower limit was 18.8%, exceeding the threshold level of 10%. The six patients in Level –1 had PR; thus, the ORR for all 25 patients treated with the study drug reached 52.0% (13 total PR, 95% CI: 31.3%–72.2%).

The secondary efficacy variables were time-to-event outcomes (the duration of response, PFS and overall survival time), 1-year survival rate, QOL and pulmonary function test. The median duration of response was 5.2 months (95% CI: 4.3–7.3 months) for the seven responders in the efficacy analysis set (Table 2). The median duration of response for the six responders at Level –1 was again 5.2 months. For the efficacy analysis set, median PFS was 4.7 months (95% CI: 1.3–6.5 months) and MST was 7.3 months (95% CI: 4.6–14.2 months, Fig. 2) with 1-year survival rate of 36.8% (95% CI: 15.2%–58.5%). Median PFS for the six patients at Level –1 was 10.1 months. MST at Level –1 could not be calculated by Kaplan–Meier method. The 1-year survival rate of Level –1 (66.7%) was beyond 50%.


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  		Table 2. Summary of time-to-event outcomes and 1-year survival rates

 

Figure 2
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  		Figure 2. Kaplan–Meier plot of overall survival in the efficacy analysis set. Solid lines, overall survival; dotted lines, high and low limits of 95% confidence interval.

 
The QOL-ACD and FACT-L measures were used for QOL evaluation. There were no major changes from prior to Cycle 1 to 3 months after Cycle 1 treatment in the mean scores for the activity and physical condition subscales of QOL-ACD (Table 3); however, mean scores from prior to Cycle 1 to 3 months after Cycle 1 treatment for the psychological condition and social relationships subscales numerically increased. The mean LCS score of FACT-L did not change substantially from prior to Cycle 1 to 3 months after Cycle 1 treatment (data not shown). These score changes indicate that QOL of the patients was maintained without worsening from baseline. Pulmonary function was also maintained with no worsening from baseline observed in the pulmonary function tests (FEV1, FVC and VC) in the efficacy analysis set (data not shown).


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  		Table 3. Summary of QOL questionnaire for cancer patients treated with anticancer drugs (Level 1, n = 19)

 
Safety
Of 25 patients of the safety analysis set, three died during the study period: one (Level 1, Step 1) from exacerbation of pneumonia as a pre-existing complication, respiratory failure, and DIC, as described earlier, and the other two (Step 2) due to study disease. Two patients experienced non-fatal serious adverse events (fever and aspiration pneumonia, respectively). A causal relationship between fever and the study drugs could not be ruled out, but the aspiration pneumonia was not considered related to study drugs. Adverse events leading to discontinuation from study treatment were observed in six patients: one patient at Level 1 and three patients at Level –1 in Step 1 and in two patients in Step 2. Adverse event leading to discontinuation in two or more patients was increased blood creatinine (two patients).

Grade 3 or more laboratory TEAEs were observed in 16 patients: four patients at Level 1 and five patients at Level –1 in Step 1 and in seven patients in Step 2. Laboratory TEAEs observed in at least half of the 25 patients were decreased-hemoglobin, decreased red blood cell count, decreased neutrophil count, decreased white blood cell count, decreased lymphocyte count, increased blood urea and decreased body weight (Table 4). Grade 3 or more non-laboratory TEAEs were observed in eight patients: three patients at Level 1 and one patient at Level –1 in Step 1 and in four patients in Step 2. Non-laboratory TEAEs observed in at least half of the 25 patients were nausea, anorexia, vomiting and malaise. No major differences between Levels 1 and –1 (Step 1) in the incidence of TEAEs were noted.


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  		Table 4. Summary of treatment-emergent adverse events (TEAEs) reported >25% patients

 
For the 19 patients at Level 1, laboratory TEAEs of grade 3 or higher, possibly related to drug, and observed in at least two patients were decreased neutrophil count (seven patients, 36.8%), decreased hemoglobin (six patients, 31.6%), decreased white blood cell count (five patients, 26.3%), decreased lymphocyte count (five patients, 26.3%), decreased platelet count (two patients, 10.5%) and decreased blood potassium (two patients, 10.5%). Non-laboratory adverse drug reactions of grade 3 or higher observed in at least two patients were vomiting (three patients, 15.8%), anorexia (three patients, 15.8%), nausea (two patients, 10.5%) and malaise (two patients, 10.5%). Adverse drug reactions of grade 3 or higher for the six patients in Level –1 were decreased neutrophil count (three patients), decreased-hemoglobin (two patients), decreased lymphocyte count (two patients) and decreased red blood cell count (one patient).


   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 Funding
 References
 
This Phase I/II study reports the first experience of the combination of pemetrexed and cisplatin therapy in Japanese patients. The RD of Pem/Cis combination therapy was established at pemetrexed 500 mg/m2 and cisplatin 75 mg/m2, with pemetrexed administration on Day 1 of each 21-day cycle followed by cisplatin, which is the same regimen used in worldwide for patients with MPM (16).

Of the 19 patients evaluable for efficacy at the RD level, there were PRs in seven patients, for an ORR of 36.8% (95% CI: 16.3%–61.6%). A pivotal Phase III study of the same regimen as that applied of the present study, yielded a response rate of 41.3% (95% CI: 34.8%–48.1%) in 225 patients (16). The response rates from both studies are comparable despite of the large difference in sample size.

The response rate of all the 25 treated patients was higher than the response rate for the 19 patients treated at the RD (52.0% versus 36.8%). This is due to the fact that all the six patients in Level –1 had PR. The excellent outcome observed in Level –1 may be attributed to differences between those patients who received the RD and those patients in Level –1 in the histological subtype of mesothelioma. All six patients in Level –1 had an epithelial subtype, which is known as a favorable prognostic factor, while only about half of the 19 patients at the RD had this subtype. In addition, the PS of the patients in Level –1 was better than the patients at RD.

A secondary efficacy endpoint MST showed 7.3 months in this study, shorter than that of the Pem/Cis arm in the Phase III study (12.1 months) (16). Although it would be difficult to compare MST of this study derived from a small sample size with the large Phase III study (n = 226), the discrepancy of survival between the two studies could be ascribed for the demographic characteristics of patients in both. There are less patients who had good prognostic factors in this study than in the Pem/Cis arm of the Phase III study: epithelial subtype: 52.6% versus 68.1%, a good PS: 21.1% (PS = 0) versus 51.8% (Karnofsky PS = 90/100) and clinical stage I/II: 8.0% versus 22.6% (16).

In this study, the most common adverse events (>50% of patients) were decreased-hemoglobin, erythropenia, neutropenia, leukopenia and lymphopenia for laboratory parameters, and nausea, anorexia, and vomiting for non-laboratory parameters. These hematologic and gastrointestinal events were similarly observed in the Pem/Cis arm of the pivotal Phase III study (16). No grade 3/4 febrile neutropenia toxicity which is a potentially life-threatening event was reported in our study. One death by pneumonitis was observed in this study; however, the patient was considered to have a pre-existing condition before initial treatment with study therapy. Adverse events observed in this study were predictable from safety profile observed in overseas trials and market experiences of pemetrexed and cisplatin combination therapy.


   CONCLUSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
Funding
 References
 
The RDs for the Pem/Cis combination are pemetrexed 500 mg/m2 and cisplatin 75 mg/m2, which is the same regimen used in worldwide for patients with MPM. The combination shows promising efficacy with an acceptable safety profile in Japanese patients with MPM.

On January 2007, Pem/Cis combination therapy was approved and launched for the treatment of patients with MPM in Japan. Intensive post-marketing surveillance in patients with MPM is ongoing.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 Funding
References
 
This study has been supported and funded by Eli Lilly Japan K.K., Kobe, Japan.

Conflict of interest statement

S.A. and Y.N. are employed by the sponsor, Eli Lilly Japan K.K.; N.S. and M.F. are paid consultants to the sponsor.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 Funding
 References
 
1 British Thoracic Society Standards of Care Committee. Statement on malignant mesothelioma in the United Kingdom. In: Thorax (2001) 56:250–65.[Free Full Text]

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8 Pass HI, Hahn SM, Vogelzang NJ, Carbone M. Benign and malignant mesothelioma-Chapter 36. DeVita VT Jr., Hellman S, Rosenberg SA, eds. (2004) 7th edn. Philadelphia: Lippincott Williams & Wilkins. 1687–715. Cancer Principles and Practice of Oncology.

9 Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer (1999) 79:666–72.[CrossRef][Web of Science][Medline]

10 Saijo N, Study Group. Guideline for phase I/II study on anticancer drugs (Draft version). Med Front (Saishin Igaku) (2001) 56:1515–41. (in Japanese).

11 Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM. Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul (1998) 38:135–52.[CrossRef][Web of Science][Medline]

12 Taylor EC, Patel HH. Synthesis of pyrazolo[3,4-d]pyrimidine analogues of the potent antitumor agent N-{4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid (LY231514). Tetrahedron (1992) 48:8089–100.[CrossRef][Web of Science]

13 The International Mesothelioma Interest Group. A proposed new international TNM staging system for malignant pleural mesothelioma. Chest (1995) 108:1122–8.[CrossRef][Web of Science][Medline]

14 The Japanese Respiratory Society. Guideline of Pulmonary Function Test. (2004) Clinical Pulmonary Functions Committee, editor. Tokyo: Medical Review. (in Japanese).

15 Van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol (2005) 23:6881–9.[Abstract/Free Full Text]

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