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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1505-1511 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.1694
Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group
From the Department of Pediatrics, Oregon Health & Science University, Portland, OR; Mayo Clinic and Foundation, Rochester, MN; Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX; Children's Oncology Group Operations Center, Arcadia, CA; Eli Lilly & Co, Indianapolis, IN; and The Children's Hospital of Philadelphia, Philadelphia, PA Address reprint requests to Suman Malempati, MD, Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, CDRC-P, Portland, OR 97239-3098; e-mail: malempat{at}ohsu.edu
Purpose We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. Conclusion Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.
Pemetrexed (LY231514, Alimta; Eli Lilly, Indianapolis, IN) is a multitargeted antifolate that inhibits the biosynthesis of thymidine and purine nucleotides1,2 through inhibition of multiple folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase (GARFT).3 After cell entry via the reduced folate carrier, pemetrexed is polyglutamated, resulting in prolonged intracellular retention and enhanced interaction with target enzymes.4,5 Thus, pemetrexed may have greater efficacy than other commonly used antifolates such as methotrexate. Pemetrexed in vitro is active in a variety of human cancer cell lines. Preclinical studies suggest that pemetrexed may have cytotoxic activity in tumor cells that are resistant to methotrexate, fluorouracil, and raltitrexed.6,7 Similar to fluorouracil and raltitrexed, the primary mechanism of pemetrexed cytotoxicity is inhibition of TS. However, cancer cell lines that overexpress TS and are resistant to other TS inhibitors remain partially sensitive to pemetrexed.8 Synergy of pemetrexed with gemcitabine, doxorubicin, and platinum compounds, as well as radiation, has been seen in cancer cell lines and animal models.9-14 In adult phase I trials, pemetrexed doses of 500 to 600 mg/m2 administered intravenously every 21 days were generally well tolerated.15,16 Myelosuppression, including grade 3/4 neutropenia, was the primary dose-limiting toxicity (DLT), whereas GI toxicities occurred in fewer than 10% of patients. Phase II studies showed that mortality was increased when GI toxicity occurred together with severe hematologic toxicity.17 In addition, patients with elevated homocysteine levels and folate deficiency experienced more severe toxicity.18 Subsequent studies in which folic acid and vitamin B12 supplements were administered have resulted in a significant decrease in severe toxicities and deaths as a result of toxicity, whereas clinical benefit was maintained.17 More recent phase I trials in adults with solid tumors in which folic acid and vitamin B12 were coadministered have found the maximum-tolerated dose (MTD) of pemetrexed, administered either as single agent or in combination, to be 1,200 to 1,800 mg/m2 (Hammond et al, manuscript submitted for publication).19,20 Several adult phase II studies have assessed activity of single-agent pemetrexed. At doses of 500 or 600 mg/m2, overall response rates of 14% to 26% have been observed in patients with breast cancer, advanced head and neck squamous carcinoma, malignant pleural mesothelioma, and advanced non–small-cell lung cancer (NSCLC).21-24 The combination of pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 produced overall response rates of 39% to 45% in patients with advanced NSCLC and 41% in patients with malignant mesothelioma.25-27 On the basis of the results of recent phase III studies, pemetrexed was approved by the US Food and Drug Administration as a second-line treatment of advanced NSCLC and as a first-line therapy in combination with cisplatin for mesothelioma.27-29 This report describes the results of a phase I trial of single-agent pemetrexed conducted by the Children's Oncology Group in pediatric patients with refractory solid tumors. The primary aims of this pediatric study were to determine the MTD, define the DLTs, and characterize the pharmacokinetics of pemetrexed administered every 21 days with folic acid and vitamin B12 supplementation. A secondary aim was to observe for antitumor activity in childhood solid tumors.
Study Population Patients older than 12 months and  21 years of age with solid tumors for which no curative or life-prolonging therapies exist were eligible for the study. Histologic verification at initial diagnosis was required except for intrinsic brainstem tumors. Additional eligibility criteria were Karnofsky (age > 10 years) or Lansky (age 10 years) performance score of  50; life expectancy of at least 8 weeks; no myelosuppressive chemotherapy within 3 weeks of study entry; at least 7 days from completion of any antineoplastic biologic agent; at least 2 weeks from local palliative radiation, 6 months from craniospinal or 50% radiation of pelvis, and 6 weeks from other substantial bone marrow radiation; no allogeneic stem-cell transplantation within 6 months of study entry and no acute graft-versus-host disease; no hematopoietic growth factors within 1 week of study entry; stable or decreasing dexamethasone dose for patients with CNS tumors; an absolute neutrophil count 1,000/µL, transfusion-independent platelet count 100,000/µL, and hemoglobin 8.0 g/dL; glomerular filtration rate or creatinine clearance 70 mL/min/1.73 m2 or normal serum creatinine for age; total bilirubin 1.5x and ALT 2.5x upper limit of normal for age; serum albumin 2.0 g/dL; no dyspnea at rest, no exercise intolerance, and pulse oximetry more than 94%. Seizure disorder was allowed only if well controlled with anticonvulsants. Patients who were pregnant or breast-feeding were excluded, as were patients with uncontrolled infections, pleural effusions, or ascites. Receipt of other investigational or anticancer agents and previous exposure to pemetrexed was not allowed. The study protocol was approved by the institutional review board of each institution from which patients were enrolled. Informed consent was obtained from the patient or their parent or guardian, and assent was obtained as appropriate, before protocol enrollment.
Study Design Patients were studied in cohorts of three to six individuals at each dose level. The starting dose was 400 mg/m2 (approximately 80% of the original adult MTD), with subsequent dose escalations occurring in increments of 30%. A minimum of three patients were studied at each dose level. If none of these three patients experienced a DLT, the subsequent three patients were enrolled at the next higher dose level. If one of three patients at a given dose level experienced a DLT, up to three more patients were treated at the same level. When DLT was observed in at least two patients in a cohort of three to six patients, the MTD was exceeded and an additional three patients were treated at the next lower dose level, provided that only three patients had been treated previously at that level. The MTD was defined as the dose level at which zero of six or one of six patients experienced DLT with at least two of three or two of six patients encountering DLT at the next higher dose.
Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0). Nonhematologic DLT was defined as any grade 3 or grade 4 toxicity attributable to pemetrexed with the specific exclusion of grade 3 or 4 nausea or vomiting; grade 3 hepatic aminotransferase (AST/ALT) elevation, which returned to
Patient Evaluation
Pharmacokinetic Studies Plasma concentrations of pemetrexed were determined at each time point using a modification of a previously described liquid chromatography tandem mass spectrometry method.31 The liquid chromatography tandem mass spectrometry system consisted of a Shimadzu liquid chromatograph (Wood Dale, IL) with two LC-10ADvp pumps (flow rate, 0.200 mL/min), and a SIL-10ADvp autoinjector (injection volume, 20 µL) coupled to a triple quadrupole Quattro Micro mass spectrometer (Waters Corp, Milford, MA) fitted with an electrospray ionization probe operating in the positive mode. Plasma samples (0.1 mL) containing pemetrexed and internal standard ([2H4]-pemetrexed) were precipitated with ice-cold methanol (0.2 mL). After vortex mixing for 15 seconds, samples were kept on ice for 15 minutes. After centrifugation (14,000 rpm for 4 minutes) in a refrigerated centrifuge set at 4°C, the aqueous-methanol supernatant was filtered through a 0.45-µm Captiva plasma protein precipitation 96-well filter plate (Varian Inc, Palo Alto, CA) into a 96–deep-well polypropylene collection plate using a 3M Empore vacuum manifold (3M, St Paul, MN) under approximately 15 to 20 inches of Hg vacuum. The sample was chromatographed under reverse-phase conditions on a Genesis C18 analytic column (2.1 x 100 mm, 3 µm particle size; Grace Vydac, Hesperia, CA) and a Brownlee NewGuard RP-18 precolumn (3.2 x 15 mm, 7 µm particle size; Perkin Elmer, Waltham, MA). The mobile phase was composed of water/acetonitrile (86:14) containing 0.2% formic acid and delivered at a flow rate of 0.2 mL/min. The injection volume was 25 µL. The source temperature, desolvation temperature, cone gas flow, and desolvation gas flow were 120°C, 350°C, 100 L/h, and 650 L/h, respectively. The dwell time, cone voltage, and collision energy values were 0.2 seconds, 30 V, and 25 eV, respectively. Pemetrexed detection was accomplished by tandem mass spectrometry using the parent ion mass-to-charge ratio of 428.1 and the daughter ion m/z of 281.1, and [2H4]-pemetrexed was analyzed using the parent ion signal of m/z 432.1 and daughter ion signal of mass-to-charge ratio of 285.1. Mass spectra and chromatograms were processed using the Quanlynx routines in the MassLynx version 3.5 software (Waters Corp, Milford, MA). Standard curves, using the peak area ratio of drug to internal standard, were linear (r2 > 0.99) over the ranges of 10 to 2,000 and 1,000 to 200,000 ng/mL. The coefficient of variation for standard values at the lower limit of quantitation (10 ng/mL) was 4.1%. Pemetrexed plasma concentration–time data were analyzed by standard noncompartmental methods using the program WINNonlin (Scientific Consultant, Apex, NC) version 4.1 (Pharsight Corp, Mountainview, CA).
From April 2004 until November 2005, 33 patients with refractory solid tumors were enrolled onto the study, of whom 31 were fully assessable for toxicity. One patient was not assessable because the parents withdrew consent for treatment before administration of the study drug. An additional patient was inassessable for nonhematologic toxicity, given that serum chemistries were not obtained on the protocol schedule. Patients were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. The median number of courses administered was one, with a range of one to 17 courses administered. Characteristics of all eligible patients are summarized in Table 1.
Toxicity The number and type of DLTs are listed in Table 2. No patient treated at 400 to 1,130 mg/m2 had DLT. DLT (grade 3 elevation of AST/ALT that did not recover before the next cycle) occurred in one of six patients treated at 1,470 mg/m2. Two of four patients treated at 2,480 mg/m2 experienced DLT, with grade 4 neutropenia and grade 3 rash occurring in one patient, and grade 3 rash, diarrhea, rectal hemorrhage and gamma-glutamyltransferase with grade 4 neutropenia, thrombocytopenia, elevated lipase, hypophosphatemia, hypokalemia, and hyponatremia occurring in a second patient. At 1,910 mg/m2, zero of six patients had DLT, defining the MTD as 1,910 mg/m2.
Non-DLTs possibly, probably, or definitely related to pemetrexed occurring in more than 10% of patients are listed in Table 3. Thirteen patients (41%) had grade 3 or 4 neutropenia with the first course of pemetrexed. Grade 3/4 thrombocytopenia, grade 3/4 leukopenia, and grade 3/4 anemia were noted in four (13%), three (9%), and five (16%) patients, respectively.
Vitamin Supplementation Before study entry, none of the patients evaluated had serum folate concentrations below the lower limit of normal, and only one patient had an elevated homocysteine concentration. Median serum folate concentrations at baseline and after vitamin supplementation were 19.7 ng/mL (range, 6.0 to 67.1 ng/mL) and 34.8 ng/mL (range, 4.3 to 127 ng/mL), respectively. Median homocysteine concentrations at baseline and after vitamin supplementation were 6.0 µmol/L (range, 2.1 to 12.1 µmol/L) and 5.4 µmol/L (range, 2.2 to 8.5 µmol/L), respectively. Baseline folate and homocysteine concentrations for the three patients who experienced DLT were not significantly different from patients without DLT (data not shown).
Antitumor Activity
Pharmacokinetics
Maximum serum concentration (Fig 1A) and AUC0-6 (Fig 1B) seemed to increase in proportion to dose for the 400 to 2,480 mg/m2 dose range. The mean (± standard deviation) plasma clearance and steady-state volume of distribution were 2.3 ± 0.7 L/h/m2 and 5.4 ± 1.3 L/m2, respectively. The harmonic mean half-life was 2.4 hours (range, 1.5 to 4 hours).
Pemetrexed has shown considerable promise both as monotherapy and combined with other neoplastic agents in phase II and III adult studies.27,29,32-35 Our study is the first to describe the toxicity profile and pharmacokinetics of pemetrexed in pediatric patients. As in recent adult studies, vitamin supplementation with vitamin B12 and folic acid, and dexamethasone for skin rash prophylaxis, were used in this study. Overall, pemetrexed was well tolerated in children. The MTD of 1,910 mg/m2 in this study is significantly higher than the recommended dose of 500 mg/m2 used for adult patients. However, recent phase I studies in adult patients, completed after the initiation of our study, have found that with folic acid and vitamin B12 supplementation, pemetrexed is well-tolerated at doses of 1,200 to 1,800 mg/m2, even in combination with other cytotoxic agents (Hammond et al, manuscript submitted for publication).19,20 Although vitamin supplementation likely enhanced the tolerability of pemetrexed, there is theoretical concern that folic acid and vitamin B12 administration may diminish the clinical activity of the study drug. However, preclinical evidence suggests that the antitumor activity of pemetrexed is maintained with concomitant administration of folic acid.36 In addition, vitamin supplementation has not diminished the efficacy of pemetrexed in studies with adults.37 The adverse effect profile of pemetrexed in children with refractory solid tumors is similar to that reported in adults. The most common toxicities in this phase I study were hematologic. Consistent with adult phase I studies, DLT was neutropenia in both patients treated at 2,480 mg/m2. Dose-limiting fatigue, which has been reported in adult studies,15,38 was not a significant adverse effect in children, although the number of children who received multiple courses of pemetrexed is limited. Dermatitis and GI toxicity, which were also seen in adults, were dose-limiting factors in one patient treated at 2,480 mg/m2. The dose-limiting electrolyte disturbances (hypophosphatemia, hyponatremia, hypokalemia) in one patient treated at 2,480 mg/m2 have not been identified as significant problems in adults.15 The pharmacokinetic data of pemetrexed in children were similar to those reported in adult patients (Table 4); a mean clearance of 2.3 L/h/m2 (approximately 3.1 L/h) compared with a typical clearance value of 3.1 L/h determined by population pharmacokinetic analysis using a nonlinear mixing effects model and a mean value of 2.3 L/h/m2 determined by compartmental analysis.31,39 Lack of objective responses in this study does not preclude additional evaluation of pemetrexed in pediatric cancers, particularly those for which antifol therapy has proven effective. Methotrexate is a critical component of osteosarcoma therapy, but resistance to methotrexate in these tumors frequently is due to altered reduced folate carrier function.40 In vitro studies suggest that sensitivity to pemetrexed persists through alternate transport mechanisms and selective GARFT inhibition in cell lines lacking reduced folate carrier.41,42 This finding, combined with the observation that a child with osteosarcoma enrolled onto this phase I study experienced disease stabilization for five cycles, supports additional evaluation of pemetrexed in children with recurrent osteosarcoma. A spectrum of antifolates, including trimetrexate,43,44 piritrexim,45,46 raltitrexed,47,48 and aminopterin,49 have undergone pediatric phase I testing. However, although trimetrexate and aminopterin have been evaluated for pediatric leukemia in phase II studies,50,51 additional clinical development of most of these nonclassical antifols in children has been limited by the cessation of clinical drug development for adult indications in the United States. Fortunately, for pemetrexed, this will not be a limitation. Given that pemetrexed inhibits multiple folate-dependent targets, including thymidylate synthetase, dihydrofolate reductase, and GARFT,3 it may have an extended spectrum of activity compared with other antifolates currently used in the treatment of pediatric cancer. The promising results of preclinical studies, favorable response rates in adult solid tumor studies, and the tolerability of this agent in children supports additional evaluation of pemetrexed for the treatment of pediatric malignancies. A Cooperative Oncology Group phase II trial of pemetrexed administered at a dose of 1,910 mg/m2 every 21 days in children with select solid tumors is planned.
Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Allen S. Melemed, Eli Lilly & Co Leadership: Allen S. Melemed, Eli Lilly & Co Consultant: N/A Stock: Allen S. Melemed, Eli Lilly & Co Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: H. Stacy Nicholson, Joel M. Reid, Susan M. Blaney, Mark Krailo, Allen S. Melemed, Peter C. Adamson Financial support: Allen S. Melemed Administrative support: Susan M. Blaney, Peter C. Adamson Provision of study materials or patients: H. Stacy Nicholson, Susan M. Blaney Collection and assembly of data: H. Stacy Nicholson, Susan M. Blaney, Ashish M. Ingle, Linda C. Stork, Renee McGovern, Stephanie Safgren, Matthew M. Ames, Peter C. Adamson Data analysis and interpretation: Suman Malempati, H. Stacy Nicholson, Joel M. Reid, Susan M. Blaney, Ashish M. Ingle, Mark Krailo, Allen S. Melemed, Matthew M. Ames, Peter C. Adamson Manuscript writing: Suman Malempati, H. Stacy Nicholson, Joel M. Reid, Susan M. Blaney, Ashish M. Ingle, Mark Krailo, Linda C. Stork, Matthew M. Ames, Peter C. Adamson Final approval of manuscript: Suman Malempati, H. Stacy Nicholson, Allen S. Melemed, Peter C. Adamson
Supported by National Cancer Institute Grant No. U01 CA97552 and National Center for Research Resources Grant No. M01 RR00188, and by Eli Lilly & Co. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clin Cancer Res 11:8089-8096, 2005 Submitted September 12, 2006; accepted January 19, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
