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Phase II Study of Pemetrexed With and Without Folic Acid and Vitamin B₁₂ as Front-Line Therapy in Malignant Pleural Mesothelioma

From the University of Turin, Department of Clinical and Biological Sciences, Torino, Italy; University of Pittsburgh, Pittsburgh, PA; University of Chicago, Chicago, IL; Dana-Farber Cancer Institute, Boston, MA; Lugenfachklinik, Immenhausen; Thorax Klinik, Heidelberg; Krankenhaus Groshansdorf, Groshansdorf; Eli Lilly and Company, Bad Homburg, Germany; Sarah Cannon Cancer Center, Nashville, TN; and Eli Lilly and Company, Indianapolis, IN.

Address reprint requests to Giorgio V. Scagliotti, MD, University of Turin, Department of Clinical and Biological Sciences, Azienda Ospedaliera S. Luigi, Regione Gonzole 10, 10043 Orbassano (Torino) Italy; email: scagliotti{at}ihnet.it.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM).

Patients and Methods: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m²) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B₁₂ supplementation to improve safety.

Results: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients.

Conclusion: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B₁₂ tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MALIGNANT PLEURAL mesothelioma (MPM) is a neoplastic disorder of the pleural lining of the lung, usually presenting at an advanced stage. Because there is no approved or generally accepted standard systemic therapy, patients commonly receive supportive care alone. In this setting, the median survival is reported to be 6 to 18 months (5-year survival, < 5%), and patients usually develop progressive pain and pulmonary compromise as the tumor gradually encases the lung.¹

Between 50% and 70% of reported cases of MPM are associated with asbestos exposure.² There is a long latency period after exposure before the disease emerges (30 to 40 years). There is now rising incidence of MPM throughout much of the world, and it is expected to peak between the years 2010 and 2020.^3,4 In industrialized countries, the incidence of MPM is two per 1,000,000 females and 10 to 30 per 1,000,000 males.¹

In light of the advanced stage and poor survival of most patients at presentation, numerous cytotoxic agents (single agent or combination) have been evaluated in phase II trials. Response rates from single-agent studies have varied widely, with most ranging from 0% to 15%, with only a few studies reporting higher rates.⁵ Median overall survival times from single-agent studies also have varied widely, with most ranging from 7 to 9 months, but a few studies have reported median overall survivals as low as 5 months and as high as 11 months.^6–11

Pemetrexed (ALIMTA; Eli Lilly and Company, Indianapolis, IN) is a new antifolate with broad antitumor activity. In vitro studies have shown that pemetrexed attacks multiple enzyme targets; namely, dihydrofolate reductase, thymidylate synthase (TS), and glycinamide ribonucleotide formyl transferase. Such targeting contrasts with the single enzyme targets of approved agents such as methotrexate, which acts on dihydrofolate reductase, and fluorouracil and raltitrexed, which inhibit TS.^12–14 Pemetrexed enters the cell primarily through the reduced folate carrier and undergoes extensive intracellular polyglutamation by folylpoly-gamma-glutamate synthetase. Long-term retention of the polyglutamated form of pemetrexed leads to persistently elevated intracellular concentrations and increased cytotoxic potential.¹⁵ Furthermore, polyglutamated pemetrexed has more than 100-fold greater affinity for TS and glycinamide ribonucleotide formyl transferase than the parent compound pemetrexed monoglutamate.¹⁶ This high affinity and long intracellular retention indicates that pemetrexed may be associated with greater clinical activity than other antifolates and TS inhibitors. This multicenter, single-cohort, phase II study was designed to determine the efficacy of pemetrexed as a single agent in chemotherapy-naive patients with advanced MPM.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with a histologically proven diagnosis of MPM who were not candidates for curative surgery were eligible for this study. Other major eligibility criteria included presence of bidimensionally and/or unidimensionally measurable lesions by computed tomography (CT) or magnetic resonance imaging; a performance status of 70 on the Karnofsky scale; an estimated life expectancy of 12 weeks; adequate bone marrow reserve (absolute neutrophil count [ANC] 1.5 x 10⁹/L, platelets 100 x 10⁹/L, and hemoglobin 9 g/dL); and creatinine clearance (CrCl) 45 mL/min as calculated by the modified Cockroft and Gault lean body mass formula. Patients with prior systemic chemotherapy were excluded from study, although prior radiation therapy was permitted. Other exclusion criteria were second primary malignancy, documented brain metastases, and inability to interrupt nonsteroidal anti-inflammatory agents.

Study Design
The primary outcome was tumor response. Secondary outcomes included duration of response, survival, time to progressive disease, time to treatment failure, quality of life (QOL), and pulmonary function tests. QOL and pulmonary function test methods and data will be presented in a separate article. This study incorporated a two-stage design¹⁷ to allow for early closure if insufficient clinical activity was evident at the end of the first stage. In the initial design, if at least two of the first 20 assessable patients achieved a response, an additional 21 patients were to be enrolled onto the second stage. Near the end of the first stage, the protocol was amended to require that all patients be supplemented with folic acid and vitamin B₁₂ until completion of study therapy in an effort to improve patient safety. In addition, at least 41 patients, rather than 21, were to be enrolled onto the second stage of study, thus ensuring that the number of patients receiving supplementation approximated the original sample size for the entire study. Fully supplemented patients were those who enrolled onto the study on or after December 10, 1999, and who received folic acid and vitamin B₁₂ supplementation throughout their treatment cycles. Nonsupplemented patients were those who started receiving study therapy before December 10, 1999, and included patients who completed study therapy without receiving vitamin supplementation and patients who received vitamins at some point after study therapy had begun.

Treatment Regimen
Pemetrexed was supplied as a 40 mg/mL aqueous solution containing 2 mg/mL of the antioxidant monothioglycerol. The starting dose (500 mg/m²) was diluted in 100 mL of normal saline for intravenous administration over 10 minutes. Drug therapy was repeated at 3-week intervals. The vitamin-supplemented patients received folic acid (350 to 1,000 µg) orally daily beginning 1 to 2 weeks before the first dose of pemetrexed and throughout the study. Vitamin B₁₂ (1,000 µg) was given intramuscularly 1 to 2 weeks before the first dose of drug and was administered approximately every 9 weeks throughout study. Dexamethasone (4 mg) or an equivalent corticosteroid was given orally twice daily the day before, day of, and day after each pemetrexed dose to prevent or reduce severity of any skin rash. To reduce risk of delayed renal clearance of pemetrexed, the ingestion of salicylates or nonsteroidal anti-inflammatory agents was not allowed during the 2 days before (5 days for long lasting agents), day of, and 2 days after treatment. Granulocyte colony-stimulating factors were given only to patients who had neutropenic fever, infection with neutropenia, or ANC less than 0.5 x 10⁹/L for at least 5 days. Leucovorin administration was allowed for National Cancer Institute Common Toxicity Criteria (version 2) grade 4 leukopenia or thrombocytopenia or for grade 4 neutropenia lasting more than 5 days.

After each dose of pemetrexed, dose adjustments were made based on platelet and neutrophil nadir counts from the previous cycle of therapy. Once a dose reduction was made, it remained reduced for all subsequent treatments. Patients with ANC less than 0.5 x 10⁹/L received a 25% dose reduction, and patients with platelets less than 50 x 10⁹/L received a 50% dose reduction. If three such dose reductions were required, the patient was discontinued from the study. In addition, if the preceding cycle of therapy resulted in grade 3 or 4 mucositis, the patient received a 50% dose reduction. If diarrhea occurred requiring hospitalization, a 25% dose reduction was made. If grade 3 or 4 nonhematologic effects occurred (with the exception of grade 3 transaminase elevation), the next cycle was delayed until resolution to grade 1 or less. If CrCl decreased to less than 45 mL/min, the next dose was delayed until it improved to 45 mL/min.

Patient Follow-Up and Measurement of Study End Points
Complete patient history, physical examination, complete blood cell count, calculated CrCl, blood chemistries, and serum vitamin deficiency markers including homocysteine were performed at baseline and before each course of treatment. Complete blood count was performed weekly while patients were on treatment. Tumor response was measured using either conventional CT scan or magnetic resonance imaging scan.

Criteria were established to allow for determination of best tumor response for patients with only bidimensionally measurable disease, only unidimensionally measurable disease, or both. A complete response (CR) was defined as complete disappearance of all measurable and assessable disease with no new lesions, disease-related symptoms, or evidence of nonassessable disease. For patients with only bidimensionally measurable disease, a partial response (PR) was defined as a 50% reduction from baseline of the sum of products of the perpendicular diameter of target lesions. For those with only unidimensionally measurable disease, a PR was defined as a 30% decrease in the sum of the greatest diameter of unidimensionally measurable target lesions. For patients with both types of measurable target lesions, one or the other criteria must have been met as indicated above, with no progression in the remaining measurable target lesions. For all response categories, there could be no new lesions, and nonmeasurable lesions must have remained stable or regressed. All objective responses were confirmed approximately 4 weeks after initial documentation. Tumor progression was defined as reappearance of a lesion, appearance of a new lesion/site, a specified degree of progression of existing measurable target lesions, worsening of assessable disease, or death from disease. For patients with only bidimensionally measurable or only unidimensionally measurable disease, progression was considered if the sum of the products of all bidimensionally measurable target disease had increased 50% over the smallest previous sum observed or if there was a 25% increase in the sum of the longest dimension of unidimensionally measurable target lesions over the smallest previous sum observed. For those with both types of lesions, one or the other criteria must have been met. Stable disease was defined at disease that did not qualify for CR, PR, or progression.

Among secondary outcomes, duration of tumor response was defined as the time from first objective status of response to the time of documented disease progression or death from any cause. Overall survival was defined as the time from date of study entry (informed consent date) to date of death from any cause. The time from study entry to the date of last follow-up was used to calculate overall survival for patients alive at the close of the study. Time to progressive disease was defined as time from study entry until time the patient progressed or death from any cause. For patients without a classification of progressive disease, the date of last follow-up was considered right-censored for purposes of these analyses. Time to treatment failure was defined as the time from study entry to the time of first observation of disease progression, death from any cause, or early discontinuation of treatment.

Statistical Methods
The proportion of patients with a PR or CR was calculated for all patients and for the vitamin-supplemented and nonsupplemented subpopulations. Ninety-five percent confidence intervals were calculated based on the F distribution.¹⁸ Survival and other time-to-event end points were analyzed using the Kaplan-Meier method.¹⁹

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
From September 1999 to November 2000, 70 patients at 10 centers in Germany, Italy, the United Kingdom, and the United States signed informed consent documents and were assessed for eligibility onto the study. Sixty-four patients met eligibility criteria; the other six patients were considered ineligible to receive study therapy (five patients did not meet enrollment criteria, and one patient withdrew informed consent).

Demographic characteristics of all 64 patients are listed in Table 1. Fully supplemented (n = 43) and nonsupplemented (n = 21) patients are listed separately. Five of the 21 nonsupplemented patients started receiving folic acid and vitamin B₁₂ after the start of pemetrexed therapy. As indicated in Table 1, the majority of patients were male, with a median age of 65 years (range, 39 to 80 years). Most patients had a diagnosis of epithelioid pleural mesothelioma at either stage III or IV (International Mesothelioma Interest Group staging system). Metastatic sites included mediastinal and other regional lymph nodes, lung, liver, chest wall, chest, peritoneum, and bone. Two patients (3.1%) had prior radiotherapy, and 30 patients (46.9%) had prior surgery, either palliative (29 patients, 45.3%) or curative (one patient, 1.6%).

Tumor Response and Time-to-Event Outcomes
Because objective tumor measurements can be difficult in MPM, two separate determinations of best tumor response were performed for each patient. Each investigator made an initial assessment of best response, and an external expert panel independently assessed the best response status of each patient at a later date. The expert panel evaluated 56 patients; eight patients were not evaluated because CT scans submitted to the panel were judged as either incomplete or of poor quality. Tumor response rates calculated from both sets of assessments are listed in Table 2. Among the investigator assessments, no patients experienced a CR; however, nine (14.1%) of the 64 patients had a PR as best tumor response. Among the 43 vitamin-supplemented patients, seven had a PR, whereas two of the 21 nonsupplemented patients had a PR. In the nonsupplemented group, one of five patients who started receiving supplementation after the start of therapy had a PR. Of the 56 patients included in the independent assessment, 10 patients had a PR as best response (17.9%). Seven responders were among the 41 patients who received vitamin supplementation, whereas the other three responders were among the 15 patients in the nonsupplemented group. All three responding patients in the nonsupplemented group started receiving supplementation after the start of therapy.

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curves of overall survival (months) for all patients and for patients by supplementation status.

Clinically important laboratory toxicities, as worst common toxicity criteria grade of toxicity, are listed in Table 4. Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. The incidence of grade 3/4 neutropenia among nonsupplemented patients was 52.4% versus only 9.3% for patients who received full vitamin supplementation. Most of the improvement in neutropenia occurred as a reduction in grade 4 severity. Liver function tests revealed elevations in bilirubin, alkaline phosphatase, and alanine transaminase for four patients. These changes were not considered clinically significant with the exception of one patient in the nonsupplemented group who developed grade 4 bilirubinemia.

There were 23 reports of serious adverse events during the study: 13 in the supplemented patients and 10 in the nonsupplemented patients. Fever (six reports) was the most commonly reported event for supplemented patients, and leukopenia and fever (three reports of each) were the most commonly reported events for nonsupplemented patients. Seven patients had an adverse event that resulted in withdrawal from study; five of these seven patients were nonsupplemented. Reasons for treatment discontinuations included arthralgia and deafness for supplemented patients and cerebrovascular accident, elevated creatinine levels, dyspnea, abnormal kidney function, and stomatitis for nonsupplemented patients.

Two deaths were reported during study therapy, both during the first cycle of therapy. Both deaths were attributed to disease progression. Two additional deaths occurred within 30 days of administration of the last dose of therapy; these were also attributed to disease progression.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Previous single-agent studies in MPM have indicated varying degrees of clinical activity with antifolates such as trimetrexate,⁶ edatrexate,⁷ and methotrexate.⁸ Results of this study show that pemetrexed has moderate antitumor activity in chemotherapy-naive MPM patients. Although the reasons for such antifolate activity in MPM patients are unclear, a recent report has described the presence of a highly expressed, high-affinity alpha folate receptor on mesothelioma cells of all histologic subtypes.²⁰ Although this type of receptor is only one of several described that can contribute to antifolate transport into cells, the highly expressed presence of such receptors may play a role in the efficient delivery of antifolates, such as pemetrexed, into mesothelioma cells.

The observed (investigator-determined) response rate of 14.1% in this study is comparable with published response rates for single agents.^5–11,21 Furthermore, the relatively large sample size, multicenter nature of this trial, and independent review of patient responses increases confidence that the response rate is a true result for this patient population.

Pemetrexed has been tested in two phase I studies in advanced MPM. In one study of 40 assessable patients, 11 patients had a diagnosis of MPM and received pemetrexed in combination with cisplatin. Five (45.5%) of 11 assessable MPM patients experienced a PR.²² In the other phase I study, all patients had a diagnosis of MPM, were chemotherapy-naive, and received pemetrexed with carboplatin.²³ Eight (32.0%) of 25 patients assessable for response had a PR.

In our tumor response rate analysis of patient subgroups defined by vitamin supplementation status, data were conflicting; vitamin-supplemented patients had an investigator-assessed response rate higher than that for nonsupplemented patients, whereas the opposite was true for the independent reviewer–assessed response rate. However, sample sizes of these subgroups were small, confidence intervals were overlapping, and CT scans were unassessable among some patients in the reviewer-assessed group. Similarly, data indicated that supplemented patients may have had some improvement in overall survival and time to progressive disease compared with nonsupplemented patients; but again, the number of patients in these subgroups is too small to justify any definitive conclusions. Thus, although patients who received vitamin supplementation were able to receive more pemetrexed, it is not clear that this translated into a true additional benefit from what pemetrexed alone provided. It is also important to note that there was no apparent adverse effect of low-dose folic acid and vitamin B₁₂ to pemetrexed therapy on tumor response rate or time-to-event outcomes.

As we have presented previously,²⁴ patients in this study who responded to therapy also experienced increases in lung volume and motility. These patients also reported improvements in QOL parameters, including dyspnea, pain, symptom distress, and functional capacity. The complete analyses of these data will be presented in a future publication.

The frequency and severity of nonhematologic and nonlaboratory toxicities were low in both vitamin-supplemented and nonsupplemented subgroups. However, supplemented patients had a marked reduction in hematologic toxicity, specifically grade 3/4 neutropenia, as well as a suggested improvement in signs and symptoms of toxicity. Overall improvement in severe toxicity after the addition of low-dose folic acid and B₁₂ also has been observed in other pemetrexed studies.²⁵ Given the favorable safety profile, convenient administration schedule, and moderate single-agent activity, pemetrexed is being investigated as a single agent in other tumor types. Two phase II non–small-cell lung cancer studies of single-agent pemetrexed resulted in response rates of 15.8%²⁶ and 23.3%.²⁷ Additional phase II pemetrexed studies in chemotherapy-naive patients with breast,²⁸ pancreatic,²⁹ and colorectal^30,31 cancer have yielded response rates ranging from 6% (pancreatic cancer) to 31% (breast cancer).

In summary, pemetrexed demonstrated modest activity as a single agent and was well tolerated, particularly in patients who received low-dose folic acid and vitamin B₁₂. A recently completed phase III study comparing pemetrexed and cisplatin versus cisplatin alone in chemotherapy-naive MPM patients should provide definitive evidence as to whether pemetrexed will become a component of standard therapy in MPM.³²

	ACKNOWLEDGMENTS

 
We thank Dr Xiaochun Li for her contribution to the statistical analyses in this study, Dr Mary Dugan for her writing and editorial skills, and Drs Elaine Gorham and Paolo Paoletti for their valuable input into the preparation of this manuscript.

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Submitted June 19, 2002; accepted January 17, 2003.

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