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© 2002 American Society for Clinical Oncology Phase I Clinical and Pharmacokinetic Study of Pemetrexed and Carboplatin in Patients With Malignant Pleural MesotheliomaByFrom the Department of Medical Oncology, Northern Centre for Cancer Treatment, Newcastle General Hospital, and Cancer Research Unit, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom; and Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN. Address reprint requests to Andy Hughes, MD, PhD, Department of Medical Oncology, Northern Centre for Cancer Treatment, Newcastle General Hospital, Westgate Rd, Newcastle Upon Tyne NE4 6BE, United Kingdom; email: andrew.hughes{at}newcastle.ac.uk
PURPOSE: To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated. PATIENTS AND METHODS: Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m2 (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL·min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m2, carboplatin AUC 6 mg/mL·min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10). RESULTS: The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m2, carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days. CONCLUSION: The MTD was pemetrexed 500 mg/m2 and carboplatin AUC 6 mg/mL·min. The recommended phase II dose of the combination is pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL·min. The combination is both active and well tolerated in MPM and deserves further exploration.
MALIGNANT PLEURAL mesothelioma (MPM) most commonly develops in the fifth to seventh decade of life and affects men more than women (five men to every one woman). MPM is increasing in incidence in most countries1; it is predicted that in Western Europe, approximately 250,000 people will die from this disease in the next 35 years. Few of the patients who undergo surgery are cured, and therefore, the focus is changing to other systemic therapies in an attempt to palliate symptoms and prolong survival. Unfortunately, to date, MPM has responded poorly to systemic therapy. There are three distinct histologic types: epithelial, sarcomatoid, and biphasic. Prognostic variables at presentation that are significantly associated with a longer survival include epithelial histology,2-4 age younger than 55 years,2,3,5 stage I disease,3,6 a normal platelet count,2,5,6 lack of chest pain,2 and pleural fluid with a pH greater than 7.30.7 Pemetrexed (Alimta; Eli Lilly, Indianapolis, IN) is a folate antimetabolite that primarily inhibits thymidylate synthase.8,9 It has also been demonstrated to inhibit both dihydrofolate reductase and glycinamide ribonucleotide formyl transferase.10 Pemetrexed gains entry into the cell via the reduced folate carrier and is an excellent substrate for folylpolyglutamate synthetase. The pentaglutamate form of pemetrexed is the predominant intracellular form and is more than 60-fold more potent in its inhibition of thymidylate synthase, and 140-fold more potent toward glycinamide ribonucleotide formyl transferase, than the monoglutamate.11 The optimal administration schedule in the clinic is a 10-minute infusion once every 21 days.12 Pemetrexed has demonstrated activity against a variety of solid tumors in clinical trials, notably non–small-cell lung,13,14 colorectal,15,16 pancreatic,17 breast,18,19 and head and neck20 cancers. In particular, five partial responses (PRs) were observed in 11 assessable patients with MPM who were treated on a phase I trial of pemetrexed and cisplatin.21 A response rate of 14.5% has been demonstrated for single-agent pemetrexed against MPM.22 The main toxicities observed with pemetrexed have been myelosuppression, rash, fatigue, diarrhea, mucositis, and reversible elevations in liver transaminase levels. Pemetrexed has also demonstrated in vitro activity in mesothelioma.23 The pharmacokinetics of pemetrexed, when administered as a single agent once every 21 days, have been examined.12 Pemetrexed demonstrates linear pharmacokinetics over a wide dose range (50 to 700 mg/m2). Elimination of pemetrexed is dependent on renal function, with 78% of the dose recovered unchanged in the urine in the first 24 hours. Mild nephrotoxicity did occur in patients treated with multiple cycles of therapy. Concurrent nonsteroidal anti-inflammatory agents have been excluded from pemetrexed trials because they may decrease the renal clearance of pemetrexed. Carboplatin is an analog of cisplatin, which has been developed and studied because of its favorable toxicity profile. Carboplatin interacts with DNA and forms both intrastrand and interstrand links. It has been studied in a wide variety of human solid tumors with impressive response rates. It has also been successfully used in combination with other cytotoxic agents. Carboplatin has been studied in patients with MPM with only modest response rates of 5% to 16%.24-26 The pharmacokinetics of carboplatin are linear, and there is a close relationship between clearance and glomerular filtration rate (GFR). Carboplatin is primarily excreted in the urine, with approximately 70% of dose excreted within 24 hours, although the majority of the drug is excreted within 6 hours. The area under the plasma concentration-time curve (AUC) for carboplatin, and consequently the toxicity and therapeutic effect of the drug, is dictated primarily by the pretreatment GFR and the dose administered. Calvert developed the following formula for the dosing of carboplatin, with AUC used as the end point27:
The dose-limiting toxicity (DLT) of carboplatin is myelosuppression, particularly thrombocytopenia, and this is closely linked to renal clearance. It is generally reversible and not cumulative when carboplatin is used as a single agent. Other toxicities observed were nausea and vomiting, mild abnormalities of liver function tests, and occasionally, anaphylactic reactions. The demand for effective treatment of advanced and metastatic cancers is increasing, particularly with combination chemotherapy regimens. We have investigated the combination of pemetrexed and carboplatin in a tumor type that remains difficult to treat. In advanced non–small-cell lung cancer, the Eastern Cooperative Oncology Group compared single-agent carboplatin with several cisplatin-based combinations. Despite a response rate of only 9%, median survival was statistically longer in the patients who received single-agent carboplatin.28 This fact, coupled with the improved toxicity profile and ease of administration, makes carboplatin an interesting choice to evaluate in combination with pemetrexed. The primary objective of this phase I dose-finding, open-label study was to determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin when given in combination to patients with MPM. The secondary objectives of the study were to determine the DLT of the drug combination, derive a recommended dose for future phase II studies, and document the antitumor activity. The pharmacokinetics of both cytotoxic agents were assessed in order to exclude potential drug interactions.
Patient Selection Up to 40 qualified patients with MPM were to be enrolled. This study was approved by the local research ethical committee. All patients gave written informed consent before being registered onto the study.
Inclusion criteria.
Patients were required to have a histologic diagnosis of MPM with no prior chemotherapy treatment. Prior radiation therapy was permitted as long as the patient had recovered from the acute toxic effects and it involved less than 30% of the bone marrow. Only patients with measurable disease and a World Health Organization performance status of 0 to 2 were eligible. Bone marrow reserve had to be adequate with an absolute neutrophil count Exclusion criteria. In addition to the common exclusion criteria used in clinical trials, patients on this study were excluded if they were unable to discontinue administration of aspirin and other nonsteroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after the dose of pemetrexed (5 days for long-acting agents). Evidence of nutritional deficiency or an albumin level less than 2.5 g/dL were also considered exclusion criteria. The latter patients were required to have a plasma homocysteine level less than 12 µmol/L because during the course of the trial, data were generated from other trials of pemetrexed that demonstrated that a raised pretreatment homocysteine level was associated with a significantly increased risk of hematologic toxicity. In fact, no patient who was recruited after this protocol modification needed to be excluded on this account. Patient monitoring. Before study enrollment, each patient had a complete history taken, a physical examination, and evaluation of World Health Organization performance status. A full blood count, urea and electrolyte concentrations, and liver function were measured. Vitamin deficiency markers (homocysteine, cystathionine, methylmalonic acid, and methylcitrate) were also measured in order to assess the influence of folate status by amino acid metabolism. A 51Cr-EDTA clearance was also obtained. Hematology and blood chemistries were routinely repeated on a weekly basis throughout the study, although these measurements could be performed more frequently by the investigator in the face of abnormal results. Vitamin deficiency markers were reassessed before each cycle of treatment. Patients underwent computed tomography (CT) scans to document disease status before treatment, and scans were repeated after every two cycles of treatment. Treatment courses were repeated every 21 days depending on the recovery of the patient from the previous course. Common toxicity criteria (CTC) for toxicity were used.
Materials Carboplatin. Carboplatin was purchased from Bristol-Myers Squibb (Hounslow, Middlesex, United Kingdom) as a 10-mg/mL solution in 15-mL (150 mg) and 45-mL (450 mg) vials. It was stored at room temperature and protected from light. It was diluted with 5% dextrose.
Methods Pemetrexed was dosed on a mg/m2 basis, whereas the dose of carboplatin was calculated to achieve a target AUC. The starting doses for the study were pemetrexed 400 mg/m2 and carboplatin AUC 4 mg/mL·min. Dose escalation then proceeded as listed in Table 1. This table provides the number of patients treated and the number of courses administered at each dose level. One patient was entered on the first dose level and observed for a full 21 days. If this patient tolerated the combination of pemetrexed and carboplatin well, further patients were then enrolled. This principle was used for each dose level. No intrapatient dose escalation was permitted on the study. The number of patients per dose level was based on any DLT experienced during cycles 1 and 2. If a DLT was observed in one of the first three patients treated at a particular dose level, three further patients were recruited. If the same DLT occurred in two of the six patients, dose escalation was discontinued and that dose defined as MTD.
DLTs were defined as the following: (1) CTC grade 4 neutropenia (absolute neutrophil count < 0.5 x 109/L) lasting  5 days, or an episode of febrile neutropenia; (2) CTC grade 4 thrombocytopenia (platelet count < 25 x 109/L); and (3) CTC grade 3 or greater nonhematologic toxicity excluding alopecia, nausea, vomiting, alkaline phosphatase, and rash, or CTC grade 3 ALT or AST. Dose escalation continued until the MTD was established. Cycles were repeated until there was evidence of disease progression or unacceptable toxicity. In addition, treatment was terminated if requested by the patient or at the discretion of the study investigator. The dose level below the MTD was to be defined as the recommended dose for phase II studies. Response assessment. The assessment of response in patients with MPM can be difficult. For the purposes of this study, all CT scans were reviewed by the same radiologist and responses measured by the use of criteria developed by Byrne et al29 for mesothelioma, which are outlined below. These criteria allow for the measurement of bi- and unidimensional disease. The thickness of pleural tumor was measured at three separate levels on transverse cuts on each thoracic CT scan. The levels chosen were those with the greatest volume of disease and with anatomic landmarks that made the level reproducible. Levels had to be at least 2 cm apart, and three levels of pleural rind were measured at each level. All bidimensionally measurable lesions were also documented. The following definitions of response were then used:
For any CR or PR observed, the response had to be confirmed with a second scan performed at least 4 weeks after the first documentation of response. Pemetrexed assay and pharmacokinetics. Plasma pemetrexed concentrations were analyzed by a liquid chromatography/mass spectroscopy/mass spectroscopy (LC/MS/MS) method.30 Plasma proteins were precipitated with a perchloric acid solution, and the supernatant was then chromatographed under reverse-phase conditions on a YMC Basic C8 column that used a gradient system with water and acetonitrile containing 0.2% formic acid. [2H4]-pemetrexed was used as the internal standard. The compounds were detected and quantified by tandem mass spectrometry with electrospray ionization. The LC/MS/MS methods for determination of pemetrexed in plasma were validated for the concentration ranges of 10 to 2,000 and 1,000 to 200,000 ng/mL using 0.5 mL of human plasma. The limit of quantitation was defined as the calibration concentration having an interday precision of ± 20% and mean accuracy of backcalculated values within ± 20% of the expected concentration.
Pharmacokinetic analysis was performed by noncompartmental methods using the WinNonlin program, version 3.1 (Pharsight, Cary, NC). The maximum plasma concentration (Cmax) and the corresponding time of the maximum concentration were identified from the measured samples and recorded. Plasma concentration-time data were plotted on a semilogarithmic scale, and the terminal log-linear phase was identified by visual inspection. The elimination rate constant ( Carboplatin assay and pharmacokinetics. Carboplatin concentrations were determined with a Philips PU9100X atomic absorption spectrophotometer (ATI Unicam, Cambridge, United Kingdom) adjusted to detect Pt (265.8 to 266 nm) as previously described.31 Blood samples were collected in heparinized tubes, and plasma was separated from cells by centrifugation (1,200 x g, 4°C, 10 minutes) within 15 minutes of blood collection. Free drug was then separated from the protein bound drug by centrifugation (1,200 x g, 4°C, 15 minutes) through an ultrafiltration membrane. Ultrafiltrate samples were either analyzed immediately or stored at -20°C before analysis. Four standard solutions of total carboplatin were prepared by serial dilution of a 1 mg/mL stock carboplatin solution in control plasma. Interrun quality assurance (QA) samples were also prepared. These quality assurance standards were stored at -20°C until required. Fifty microliters of each standard/sample to be analyzed was placed in a plastic atomic absorption vial (S.H. Scientific, Blyth, United Kingdom), to which was then added 0.95 mL of 0.1 M HCl. The resulting solutions were then thoroughly mixed with a pipette (Gilson, Anachem, Bedfordshire, United Kingdom). The three calibration samples were used to calibrate the atomic absorption spectrophotometer, and the calibration was checked by running the QAs directly afterward. The atomic absorption spectrophotometer was recalibrated after every 10 patient samples. The observed carboplatin AUC (mg/mL·min) was estimated using WinNonlin as above.
Patient Characteristics Twenty-nine patients were enrolled onto this study, although two patients never received treatment due to deteriorating clinical conditions. The individual characteristics of the 27 patients treated are summarized in Table 2. Twenty-three patients were men, and age ranged from 39 to 78 years (median age, 58 years). Seventeen patients (63%) had stage IV disease, and eight (30%) had stage III disease according to the International Mesothelioma Interest Group staging classification.32 All pathology was independently reviewed, and the majority of patients (59%) had epithelial histology. It was deemed too difficult to subtype MPM in four patients. In two of these four patients, the diagnosis of MPM was most likely but not entirely diagnostic. Of the 27 patients that received treatment, six were younger than 55 years of age. Twenty patients had a normal platelet count, and nine were free of chest pain at presentation. All patients were symptomatic at initiation of chemotherapy.
Dose Escalations As can be observed in Table 1, six patients were recruited onto the study at dose level 1. The first patient treated experienced grade 4 thrombocytopenia after two courses of treatment, but this was proven to be due to the development of idiopathic thrombocytopenic purpura. Our hematology colleagues did not think that this was likely a drug-related event. This event was therefore not classed as a DLT, but it was thought prudent to expand the dose level to six patients in the interest of patient safety. The combination was well tolerated, and dose escalation therefore proceeded to level 2. On dose level 2, four patients were treated in total because the third patient died after one course of treatment from an acute cardiac event, again thought to be non–drug-related. A further patient was therefore enrolled. No DLTs occurred in the first three patients treated on dose level 3, and the trial proceeded to accrue at the next dose level. Dose level 4 was actually the top dose level on the original protocol, and the three patients treated at this dose tolerated the treatment well, with no DLTs observed. It was then decided to further explore dose level 3, because pemetrexed 500 mg/m2 had by then become the standard dose on all pemetrexed combination studies. In total, nine patients were treated at pemetrexed 500 mg/m2 and carboplatin AUC 5. No DLTs were observed, proving that these doses could be safely used in combination. A further dose level was then introduced (level 5), which escalated the carboplatin dose to AUC 6. Five patients were treated on this level, which was determined to be the MTD because three patients developed DLTs at this level.
Toxicity
Even at the first dose level, three of the six patients experienced at least grade 3 neutropenia. However, this only corresponded to 14% of the total courses and there were no DLTs observed. Five of the seven courses associated with grade 3 or 4 neutropenia were experienced by patient no. 6, on courses 6 to 10 inclusive. Only one patient experienced leukopenia greater than grade 2. Four patient courses (8%) were complicated by grade 3 thrombocytopenia, although no clinical problems resulted. Grade 3 anemia was observed on two patient courses. At the second dose level, myelosuppression was again common although uncomplicated. Of the four patients treated, three experienced at least grade 3 neutropenia (90% of courses), although this was characteristically short-lived. Three patients also experienced grade 3 thrombocytopenia, although no bleeding complications were observed and no platelet transfusions were required. Three courses were complicated by grade 3 anemia. Nine patients were treated on dose level 3. Five experienced at least grade 3 leukopenia and six at least grade 3 neutropenia. Despite this, only 32% and 38% of courses were associated with the respective toxicities. Six patients developed at least grade 3 thrombocytopenia, although only 20% of courses were affected. The thrombocytopenia was more of a problem in the later courses for each patient. Four courses were associated with grade 3 anemia. Dose level 4 was well tolerated with respect to platelet count. Of the 17 courses administered, one was complicated by grade 4 thrombocytopenia, and there were no incidences of grade 3 thrombocytopenia. Neutropenia and leukopenia were far more common, although again, there were minimal clinical complications. All three patients experienced at least grade 3 neutropenia with 65% of courses affected. Leukopenia of grade 3 severity was noted in 24% of courses. On the top dose level, five patients received 27 courses of treatment. Three patients experienced at least grade 3 leukopenia (33% of all courses), whereas four patients developed at least grade 3 neutropenia (37% of all courses). Six courses were complicated by grade 3 or 4 thrombocytopenia and three by grade 3 anemia. Three patients experienced a DLT after either the first or second course of treatment. Two patients experienced grade 4 neutropenia lasting for more than 5 days, and the third was admitted to the hospital with neutropenic sepsis. This dose level (pemetrexed 500 mg/m2, carboplatin AUC 6) was therefore the MTD. Nonhematologic toxicity. Nonhematologic toxicity was not a major problem on this study. The incidence of major nonhematologic toxicities—nausea, vomiting, diarrhea, stomatitis, and rash—are listed in Table 5. There were no toxicities greater than grade 2 on dose level 1. Only five patient courses (10%) were complicated by nausea of any description and only six (12%) by stomatitis. The incidence of rash at this dose level and indeed, in the study as a whole, was minimal and probably related to the prophylactic use of dexamethasone 4 mg bid for 3 days, starting the day before treatment.
On dose level 2, two patient courses (10%) were complicated by grade 3 nausea and one (5%) by grade 3 vomiting. One patient experienced grade 3 nausea and grade 3 vomiting with his only course of treatment but died a non–drug-related death before his second course was due. With the exception of three episodes of grade 2 and one episode of grade 3 increases in bilirubin (all of which normalized before the next treatment course and which occurred in the same patient), no other toxicities greater than grade 2 were observed in the 20 courses administered on this dose level. Fifty courses were administered on dose level 3. Ten courses (20%) were associated with grade 2 nausea and only three (6%) with grade 3. There were no incidences of grade 3 vomiting, and only three courses (6%) were complicated by grade 2. Twenty-one patient courses (42%) were associated with stomatitis, with two (4%) of grade 3 severity. Increasing the dose to level 4 had no increased effect on nonhematologic toxicity. Indeed, there were no grade 3 toxicities observed for any of the 17 patient courses, except for grade 3 increases in bilirubin, which all occurred in the same patient and all levels normalized before the next cycle. On dose level 5, the majority (70%) of courses were complicated by nausea of some description, although few by grade 2 or 3 (22%). Eight courses (30%) were associated with vomiting, six (22%) of which were of grade 1 severity only. Stomatitis was experienced in 19 patient courses (70%), although only one course (4%) reached grade 3 severity. There were no other grade 3 toxicities observed on this dose level. Although transient increases in transaminase levels have been commonly observed in previous studies with pemetrexed, only two courses in the whole study were complicated by grade 3 transaminase toxicity. Transaminase levels on each occasion normalized quickly and the next course of treatment was given on time.
Response Each of the 27 patients treated experienced cancer-related symptoms at the start of chemotherapy, most notably dyspnea, cough, and chest pain. Nineteen patients (70%) reported an improvement in symptoms when directly questioned while on study, and some of these improvements were dramatic. Of these patients, 16 (84%) had improved symptoms after only two courses of chemotherapy. A selection of CT responses is demonstrated in Figs 1 and 2. Interestingly, five of the eight PRs occurred in patients treated on the first two dose levels. These data are listed in Table 1.
Survival The time between start of chemotherapy and time to PD (or time when last seen if the disease had not progressed) and time to death have been calculated for each patient. These results have been used to generate data for progression-free survival and overall survival. These data are represented graphically in Fig 3. Currently, nine of 27 patients treated are still alive, with survival ranging from 618 to 1,064 days.
One patient received 10 courses of chemotherapy with a PR that was maintained 27 months after completing his treatment (ie, 35 months from beginning chemotherapy). The median time to progression was 305 days, and the median survival was 451 days. As was observed, there was no striking relationship between age less than 55 years, normal platelet count, and a lack of chest pain at presentation, and response or prolonged survival. There was no obvious trend toward a poorer prognosis for the patients with either biphasic or sarcomatoid histologic subtypes. However, of the 27 patients treated, only two were sarcomatoid and five biphasic subtypes. The majority (93%) of patients had at least stage III disease, and five of the eight responses occurred in patients with stage IV disease.
Pharmacokinetics
The pharmacokinetic data for pemetrexed (Table 7) are comparable to previous historical values observed that use this schedule as a single agent. Although the pemetrexed AUC and peak plasma concentrations seemed to be disproportionately lower at the 400-mg/m2 dose when compared with the higher doses, this may be explained by the higher EDTA GFR observed pretreatment. The mean (± SD) EDTA GFR (Table 7) for the 400-, 500-, and 600-mg/m2 pemetrexed dose levels were 144 ± 34, 107 ± 23, and 113 ± 26 ml/min, respectively. The terminal elimination half-life was consistent across the dose groups. Pemetrexed clearance increased with improved renal function as assessed by EDTA GFR (Fig 4), consistent with the route of elimination of the drug. Renal function seemed to diminish for the majority of patients with each successive course of chemotherapy. The mean pretreatment EDTA GFR was 122 mL/min compared with a mean GFR at the end of treatment of 93 mL/min. Although this finding reached statistical significance (P < .001, paired t test), the authors thought that this had no major clinical significance.
MPM is a disease that is normally resistant to chemotherapy and is increasing in incidence. The activity observed against this tumor in a phase I study of pemetrexed and cisplatin21 led to the design of the current study. Potential advantages to the use of carboplatin rather than cisplatin include its better side effect profile and ease of administration. Carboplatin and pemetrexed have single-agent activity against MPM. A phase I dose-escalating study was performed, and the MTD was found to be pemetrexed 500 mg/m2 and carboplatin AUC 6. Three DLTs (all hematologic) were observed in the five patients treated at this dose level. Although the fourth dose level (pemetrexed 600 mg/m2, carboplatin AUC 5) was well tolerated, the dose of pemetrexed that has become standard for phase II clinical trials is 500 mg/m2. Therefore, the recommended dose for phase II trials is pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL·min. This was the third dose level in this study and demonstrated an acceptable toxicity profile. The AUC of 5 for carboplatin represents a full dose of the drug. Thus, pemetrexed and carboplatin can be combined in this population of patients without compromising the dose of either agent. The major toxicities observed were neutropenia, leukopenia, and thrombocytopenia. These were generally short-lived and caused few clinical problems. The median number of courses of treatment was six (range, one to 10 courses), and this is much higher than is generally the case for phase I clinical trials. This reflects the excellent tolerability of the drug combination, the presence of clinical benefit in the majority of patients, and possibly the chemotherapy-naive nature of the population. The effect of folic acid on modulating the toxicity and antitumor efficacy of pemetrexed has been studied using several human tumor cell lines.34 Folic acid supplementation was demonstrated to preserve the antitumor activity of pemetrexed while reducing toxicity. As a result of these observations, pemetrexed is now routinely administered with vitamin supplementation in the form of daily folic acid and regular vitamin B12 injections.35 However, because these observations had not been finalized when this study began, vitamin supplementation was not included in this study. The phase I response rate of 32% observed for these patients with MPM is certainly most encouraging. As a single agent, carboplatin, has demonstrated response rates of 5% to 16%, and pemetrexed 14.5%. The combination of carboplatin and pemetrexed would therefore seem to be synergistic, and the response rate is certainly comparable with any combination chemotherapy regimen tested in this disease type. It is interesting that an in vitro synergistic effect has been demonstrated when pemetrexed is administered before oxaliplatin in colorectal carcinoma cells.36 No potentiation was found with the reverse sequence of drug administration. Few drugs have activity in MPM, although the antimetabolites, and in particular antifolates, would seem to be the most active class of drugs for this disease. The activity of the combination used in this clinical study is therefore perhaps not surprising. Overexpression of the alpha folate receptor in mesothelioma is thought to account for the relatively high activity of the antifolates in this disease.37 Of the other antifolate drugs, methotrexate, in combination with mitoxantrone and mitomycin, demonstrated a response rate of 32%, with an overall median survival of 13.5 months.38 High-dose methotrexate, in combination with interferons, is also an active combination with a response rate of 29% and median survival of 17 months.39 The combination of methotrexate and vinblastine, with or without platinum, also demonstrated activity.40 A combination of raltitrexed (3 mg/m2) and oxaliplatin (130 mg/m2) every 21 days has been studied. Fifty-eight patients have been evaluated for efficacy, and 15 PRs have been observed, for a response rate of 26%. Median time to progression was 4.5 months, and median survival has not yet been reached.41 Edatrexate is moderately active against mesothelioma,42 whereas trimetrexate only demonstrated minor activity.43 An international randomized phase III registration trial comparing pemetrexed and cisplatin with pemetrexed and placebo has been completed. This study enrolled 430 patients with MPM and is the largest phase III trial to date in this disease. Three other large international randomized phase III trials are ongoing. These trials are investigating raltitrexed and cisplatin versus single-agent cisplatin; doxorubicin and ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) versus single-agent doxorubicin; and vinorelbine versus mitomycin, vinblastine, and cisplatin versus best supportive care, respectively. Because of the increasing incidence of MPM, and because no standard chemotherapy exists, much work is also being done to investigate the potential of other newer chemotherapy agents. Docetaxel, at a dose of 100 mg/m2 every 21 days, has been studied in two separate phase II studies as a single agent. In the first study, only one of 19 assessable patients responded and the study was terminated.44 A study in South Africa demonstrated more impressive activity, with five PRs in 22 assessable patients for a response rate of 23%.45 Irinotecan at a dose of 125 mg/m2 weekly for 4 weeks every 42 days caused considerable toxicity and demonstrated no antitumor activity.46 Docetaxel and irinotecan were tested in combination with no responses in 15 patients.47 The toxicity experienced was severe. Twenty-nine patients with MPM were treated with vinorelbine 30 mg/m2 every 7 days until disease progression. A response rate of 24% was observed.48 Gemcitabine has been studied in three separate phase II studies as a single agent. In a United States study, gemcitabine was administered at a dose of 1,500 mg/m2 on days 1, 8, and 15 every 28 days. Of 17 assessable patients, there were no objective responses and median overall survival was only 4.7 months.49 An European Organization for Research and Treatment of Cancer study examined gemcitabine at a dose of 1,250 mg/m2 on days 1, 8, and 15 every 28 days. The response rate was 7% with a median survival of 8 months.50 The dose of gemcitabine in a German study was also 1,250 mg/m2 days 1, 8, and 15 every 28 days. In this study, there were five responses observed (one CR, four PR) in the 16 assessable patients.51 An Australian study has investigated the combination of cisplatin and gemcitabine.29 The doses used were cisplatin 100 mg/m2 on day 1 and gemcitabine 1,000 mg/m2 on days 1, 8, and 15. Cycles were repeated every 28 days. Of 21 patients treated, there were 10 PRs for an impressive response rate of 47.6%. Median response duration was 21 weeks, progression-free survival was 22 weeks, and overall survival was 27 weeks. A follow-up study that used an identical drug regimen in a multicenter setting demonstrated a response rate of 26%.52 Response duration and survival were similar. The combination of carboplatin (AUC 5, provided on day 1) and gemcitabine (1,000 mg/m2 on days 1, 8, and 15) administered every 28 days revealed a response rate of 16% with a median overall survival of 8.6 months.53 It is interesting that there seems to be more clinical activity with cisplatin plus gemcitabine, cisplatin plus irinotecan,54 and cisplatin or carboplatin in combination with pemetrexed, compared with any of the drugs used as single agents. In summary, the combination of pemetrexed and carboplatin is an active and well-tolerated regimen in the treatment of MPM. The response rate was 32%, and the disease-free and overall survival is impressive. The MTD was pemetrexed 500 mg/m2 and carboplatin AUC 6 mg/mL·min. The recommended phase II dose is pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL·min, which, with the advent of vitamin supplementation, is likely to cause few major side effects. It is also of interest that the combination of pemetrexed and cisplatin has been reported as having a response rate of 45% in non–small-cell lung cancer,55 suggesting that the carboplatin combination may be active in this indication as well. Further investigation of this potent drug combination is certainly warranted.
We thank David Readett, Nick Botwood, Paolo Paoletti, Elaine Gorham, Jim Krull, Rachel Edwards, Fiona Chapman, Marylyn Pilkington, Dorothy Simmons, Madeleine Proctor, John Wilsdon, Allan Stevenson, and Alistair Burt.
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ABSTRACT
INTRODUCTION
1.5 times the upper limit of normal, and AST and ALT were 
) was determined as the slope of the linear regression for the terminal log-linear portion of the concentration-time curve. A terminal half-life value was calculated as ln(2)/
