Clinical Study Received: July 16, 2014 Accepted after revision: October 18, 2014 Published online: December 6, 2014
Oncology 2015;88:201–207 DOI: 10.1159/000369255
Dose Escalation and Pharmacokinetic Study of Carboplatin plus Pemetrexed for Elderly Patients with Advanced Nonsquamous Non-Small-Cell Lung Cancer: Kumamoto Thoracic Oncology Study Group Trial 1002 Shinya Sakata a Jiichiro Sasaki g Sho Saeki a Akinobu Hamada b Hiroto Kishi c Kazuyoshi Nakamura d Hideyuki Tanaka d Daisuke Notsute f Ryo Sato a Koichi Saruwatari a Toyohisa Iriki e Kimitaka Akaike f Shinji Fujii e Susumu Hirosako a Hirotsugu Kohrogi a
Department of Respiratory Medicine, Kumamoto University Hospital, b Department of Clinical Pharmaceutical Science, Kumamoto University, c Department of Respiratory Medicine, Kumamoto City Hospital, d Department of Respiratory Medicine, Taragi Municipal Hospital, and e Division of Respiratory Disease, Kumamoto Regional Medical Center, Kumamoto, f Department of Internal Medicine, Miyazaki Prefectural Nobeoka Hospital, Miyazaki, and g Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kanagawa, Japan
Key Words Nonsquamous non-small-cell lung cancer · Elderly subjects · Carboplatin plus pemetrexed · Dose escalation · Pharmacokinetics
Abstract Objectives: This study was designed to determine the recommended dose of carboplatin and pemetrexed for elderly (≥70-year-old) chemotherapy-naïve patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of pemetrexed. Methods: The patients were treated with 4–6 cycles of carboplatin plus a fixed dose of pemetrexed (500 mg/m2) every 3 weeks; the dose of carboplatin was escalated [from area under the curve (AUC) 4 to AUC 6]. To examine the pharmacokinetics of
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pemetrexed, blood samples were collected before and after pemetrexed infusion, and the blood levels of pemetrexed were measured by liquid chromatography-mass spectrometry. Results: Grade 3 infection as a dose-limiting toxicity was observed at a carboplatin dose of AUC 6. We therefore determined a carboplatin dose of AUC 5 and a pemetrexed dose of 500 mg/m2 as the recommended doses from this study. The pharmacokinetic study showed a significant inverse correlation between the AUC of pemetrexed and the creatinine clearance. Conclusions: For elderly chemotherapy-naïve patients with advanced nonsquamous NSCLC, the combination of carboplatin AUC 5 plus pemetrexed 500 mg/ m2 is recommended as a promising regimen; however, a reduction of the pemetrexed dose may be required for patients with renal dysfunction because of the high risk of hematotoxicities. © 2014 S. Karger AG, Basel
Dr. Hirotsugu Kohrogi Department of Respiratory Medicine, Kumamoto University Hospital Faculty of Life Sciences, Kumamoto University 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556 (Japan) E-Mail kohrogi @ kumamoto-u.ac.jp
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The populations of both elderly patients with nonsmall-cell lung cancer (NSCLC) and elderly individuals in the general population are increasing around the world, including Japan. Because the renal blood flow decreases with aging, elderly cancer patients receiving chemotherapy have a high incidence of renal dysfunction . Consequently, the development of a new treatment option is needed for this population. Several clinical trials have been conducted to develop a standard chemotherapy for elderly patients with advanced NSCLC. A large-scale randomized controlled trial comparing vinorelbine (VNR) as a single agent with best-supportive care indicated prolonged survival and an improved quality of life in the VNR arm . In addition, docetaxel showed an equivalent survival benefit to that afforded by VNR in the Japanese study WJTOG9904 . In contrast, in the Multicenter Italian Lung Cancer in the Elderly Study (MILES), combined VNR plus gemcitabine (GEM) therapy failed to show any improvement in efficacy over that of VNR or GEM administered as single agents . These results suggest that for elderly patients with advanced NSCLC, standard chemotherapy consists of single-agent treatment with an agent such as VNR, GEM or docetaxel. The standard therapy for nonelderly NSCLC patients without EGFR mutation is platinum-containing combination chemotherapy. Recently, in the IFCT0501 study, carboplatin plus weekly paclitaxel was found to provide a survival benefit to elderly patients with NSCLC (progressionfree survival: 6.0 vs. 2.8 months, p < 0.0001; overall survival: 10.3 vs. 6.2 months, p < 0.001) as compared to single-agent treatment with the aforementioned drugs, although it was associated with an incidence of treatment-related deaths of 4.4% . In contrast, another phase III trial (JCOG0803/ WJOG4307L) which was designed to evaluate weekly cisplatin plus docetaxel as compared to docetaxel alone for elderly NSCLC patients failed to show any improvement in survival in the combination therapy arm. Pemetrexed, a potent multitargeted antifolate, inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, all of which are involved in the de novo synthesis of purines and pyrimidines. In a phase III study conducted in 2008 that compared cisplatin plus pemetrexed with cisplatin plus GEM, the median survival time in both treatment arms was equal (10.3 months), and the noninferiority of pemetrexed to GEM for combined administration with cisplatin was confirmed . In addition, a subset analysis according to the histologic type revealed that pemetrexed 202
Oncology 2015;88:201–207 DOI: 10.1159/000369255
plus cisplatin afforded a greater survival benefit to patients with nonsquamous NSCLC . While cisplatin plus pemetrexed is the standard treatment for nonsquamous NSCLC, carboplatin-containing regimens have been widely used as a substitute for cisplatin-containing regimens because of the lower incidence of nonhematotoxicity associated with the latter. While a number of phase II and III studies have already been performed on patients with a mean age of 62–66 years to estimate the safety and efficacy of combined carboplatin plus pemetrexed therapy for NSCLC [7, 8], only one study to evaluate the safety and efficacy of this combination therapy has been reported for elderly patients . Pemetrexed is not metabolized to any appreciable extent in the body and is primarily excreted in the urine, with 70–90% of the administered dose recovered in unchanged form within the first 24 h following administration. The total systemic clearance of pemetrexed is 91.8 ml/min, and its elimination half-life is 3.5 h in patients with normal renal function (creatinine clearance: ≥90 ml/min). However, the pharmacokinetics of pemetrexed in elderly patients has not yet been investigated. In the present study, to establish the suitable doses of pemetrexed and carboplatin for elderly patients with nonsquamous NSCLC, we conducted this phase I dose escalation study and also examined the pharmacokinetics of pemetrexed in elderly (≥70-year-old) chemotherapynaïve patients. The primary objectives of this study were to evaluate the incidence and severity of adverse events and to determine the recommended dose (RD) of carboplatin for use in combination with pemetrexed. In addition, we investigated the pharmacokinetics of pemetrexed. The University Hospital Medical Information Network (UMIN) ID for this study is 000004629. Patients and Methods Study Design The study subjects were divided into 3 cohorts: (1) cohort 0 (level 1) patients, receiving a carboplatin dose of area under the curve (AUC) 4 according to Calvert’s formula plus pemetrexed, (2) cohort 1 (level 2) patients, receiving a carboplatin dose of AUC 5 plus pemetrexed, and (3) cohort 2 (level 3) patients, receiving a carboplatin dose of AUC 6 plus pemetrexed. In each cohort, if only 1 out of the 3 patients exhibited a dose-limiting toxicity (DLT), 3 additional patients were treated at the same dose level. Dose escalation was continued if a DLT was observed in no more than 1 of the 6 patients. If 2 out of the initial 3 patients or at least 2 out of the 6 patients experienced a DLT, the dose level was considered to be the maximum tolerated dose (MTD), and 1 dose level under that level was considered the RD. The RD was determined taking into consideration the incidence of adverse events and the validity of
Sakata et al.
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Inclusion and Exclusion Criteria Elderly patients (≥70 years old) with histologically or cytologically confirmed nonsquamous NSCLC were eligible for this study. Each patient met the following criteria: (1) clinical stage IIIB or IV or postoperative recurrence; (2) chemotherapy naïve; (3) ≥70 years of age; (4) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (5) adequate functioning of the major organs (white blood cell count: ≥3,500/mm3; neutrophil cell count: ≥1,500/ mm3; platelet count: ≥100,000/mm3; hemoglobin: ≥9.0 g/dl; liver function: AST and ALT less than or equal to twice the upper limit of normal; total bilirubin: ≤1.5 mg/dl; predicted creatinine clearance or 24-hour creatinine clearance: ≥50 ml/min, as estimated using the Cockcroft and Gault formula, and PaO2 ≥60 Torr or SpO2 ≥90%); (6) measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), and (7) life expectancy >3 months. Patients who met the following criteria were excluded from this study: (1) histological diagnosis of squamous cell carcinoma; (2) previous history of radiation therapy for the primary tumor; (3) superior vena cava syndrome; (4) massive or uncontrollable pleural effusion; (5) interstitial pneumonia diagnosed on a chest X-ray; (6) symptomatic brain metastasis, and (7) mental disorder with clinical implications. This study was performed in accordance with the ethical principles outlined in the Declaration of Helsinki, and the local institutional review board approved this protocol before the initiation of the study. Written informed consent was obtained from all patients prior to their enrollment in the study. Study Treatments All patients received pemetrexed at a fixed dose of 500 mg/m2 as a 10-min intravenous infusion, followed by intravenous infusion of carboplatin (AUC 4, 5 or 6) over 60 min. The combination chemotherapy was repeated every 3 weeks for a maximum of 6 courses. During the period of this study, they received an oral dose of 0.5 mg of folic acid once a day and 1 mg of vitamin B12 by intramuscular injection every 9 weeks. The protocol treatment was provided for up to 6 courses, in case the patients showed complete response (CR), partial response (PR) or stable disease (SD) according to the RECIST version 1.1 criteria for the duration of the treatment. If the patients responded (CR, PR or SD) to this treatment regimen, no other treatment for the lung cancer was undertaken after the completion of the treatment, except for palliative medicines, until a recurrence occurred. On the other hand, no treatment restriction was placed for patients with progressive disease after the completion of the study treatment.
thrombocytopenia referring to our previous phase I study on the basis of clinical practice ); (4) nonhematological toxicity grade ≥3 (except for nausea, vomiting, anorexia, fatigue or hypersensitivity), or (5) start date of the following course of chemotherapy >5 weeks after the start date of the previous cycle of chemotherapy. Assessment Procedures and Efficacy Evaluation An evaluation by chest CT or MRI, abdominal CT, brain MRI and bone scintigraphy or FDG-PET was performed within 4 weeks prior to the start of the treatment. An examination by chest X-ray, blood tests, biochemical tests, tumor marker measurements, electrocardiography and blood gas analysis or pulse oximetry was performed within 2 weeks prior to the start of the study treatment. An assessment of the patient’s medical history and a general physical examination were performed within 1 week prior to the start of the study treatment. A general physical examination, blood tests, biochemical tests and blood gas analysis or pulse oximetry were performed every 2 weeks during the protocol treatment. A chest CT or MRI was performed every 6–8 weeks. The antitumor effect of the treatment was evaluated according to the RECIST version 1.1 criteria. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 were used for the safety evaluation. Pharmacokinetics of Pemetrexed Blood samples were collected during the first cycle of treatment, before the pemetrexed infusion as well as 10 min and 2, 4, 6, 8, 12 and 24 h after the infusion in tubes containing EDTA as the anticoagulant. The levels of pemetrexed in the blood samples were measured by liquid chromatography-mass spectrometry. Tandem mass spectrometry was performed using an API 3200 triple quadrupole mass spectrometer (AB Sciex, Tokyo, Japan). The electrospray ionization source was operated in the positive ion mode. Analyst software version 1.5.1 was used for instrument control and data analysis. The HPLC system (Shimadzu Prominence series) consisted of a system controller (CBM-20 A), 2 binary pumps (LC20 AD), an autosampler (SIL-20 AC HT), a column oven (CTO-20 A) and a vacuum degasser (DGU-20 A3; Shimadzu, Kyoto, Japan). Statistical Analysis Potential relations between the AUC of pemetrexed and the patients’ creatinine clearance as well as the AUC of carboplatin were evaluated from the results of the pharmacokinetic analysis. The significance of differences in the AUC of pemetrexed between patients with high, middle and low creatinine clearance values was evaluated by the nonparametric Mann-Whitney U test. The significance of differences in the AUC of pemetrexed between patients receiving carboplatin at the doses of AUC 4, 5 and 6 was also investigated by the nonparametric Mann-Whitney U test. A p value of 0.05 (one-tailed distribution) was considered to indicate a statistically significant difference.
Definition of DLT DLT was defined as a toxicity occurring during cycle 1 that met 1 of the following criteria and for which a causal relationship to the study drugs could not be ruled out: (1) grade 4 reduction in white blood cell count (count 3 days or grade 4 reduction in neutrophil count (count