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Originally published as JCO Early Release 10.1200/JCO.2004.00.9720 on January 3 2006 © 2006 American Society of Clinical Oncology. Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients With Normal and Impaired Renal FunctionFrom the Institute for Drug Development at the Cancer Therapy and Research Center; Nuclear Medicine Department, The University of Texas Health Science Center, San Antonio, TX; Indiana University Cancer Center; and Eli Lilly and Company, Indianapolis, IN. Address reprint requests to Chris H. Takimoto, MD, PhD, Institute for Drug Development, Cancer Therapy and Research Center; 7979 Wurzbach Rd, 4th Floor Zeller Building, San Antonio, TX, 78229; e-mail: ctakimot{at}idd.org
PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function.
PATIENTS AND METHODS: Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from
RESULTS: Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and nonsupplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR
CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR
Pemetrexed (LY231514; Alimta, Eli Lilly and Co, Indianapolis, IN) is a novel antifolate that inhibits multiple enzymes involved in purine and pyrimidine synthesis. Pemetrexed has a unique pyrrolopyrimidine nucleus, which distinguishes it from methotrexate and other antifolates.1 Compared with methotrexate, pemetrexed has a higher affinity for folypoly-  -glutamate synthetase.2 This results in the prolonged retention of pemetrexed polyglutamates within cells, thereby enhancing its interaction with target enzymes. Initially, pemetrexed was found to be a specific inhibitor of thymidylate synthase3,4; however, it was recognized subsequently as a potent inhibitor of other key folate-dependent enzymes including dihydrofolate reductase and glycinamide ribonucleotide formyl transferase.5 These multiple mechanisms of action may explain the greater potency and broader spectrum of antitumor activity of pemetrexed in preclinical studies compared with other antimetabolites such as fluorouracil, methotrexate, or raltitrexed.5,6 In clinical studies, antitumor activity has been observed in patients with malignant mesothelioma and non–small-cell lung cancer (NSCLC), as well as colorectal, pancreatic, bladder, head and neck, cervical, gastric, and breast carcinomas.7-14 Pemetrexed has received regulatory approval in combination with cisplatin for chemotherapy-naive patients with malignant mesothelioma and as a single agent for second-line therapy in advanced NSCLC patients.15,16 In phase I dose-escalation trials, a 10-minute intravenous infusion of pemetrexed was evaluated using three different schedules: weekly for 4 of 6 weeks, once daily 5 days a week every 3 weeks, and once every 3 weeks.17-19 The principal dose-limiting toxicities (DLTs) for all schedules included neutropenia, thrombocytopenia, fatigue, and dermatitis. Other toxicities consisted of nausea and vomiting, anorexia, diarrhea, and transient elevation of hepatic aminotransferases. On the basis of phase I study results, the recommended phase II dose of single-agent pemetrexed administered without vitamin supplementation was 600 mg/m2 infused over 10 minutes every 21 days.19-21 A subsequent phase II study prompted reduction of the pemetrexed dose recommended for additional evaluation to 500 mg/m2 when a large percentage of patients experienced severe toxicities.8 Pemetrexed is rapidly eliminated (half-life, 3.5 hours; total systemic clearance, 91.8 mL/min), mainly via the kidneys, with 70% to 90% of the administered drug recoverable in the urine within 24 hours.20-22 Plasma protein binding of pemetrexed is approximately 80%, and the volume of distribution at steady-state is small (approximately 16 L), which is consistent with limited tissue distribution.20-22 Because pemetrexed is eliminated by renal excretion, this phase I dose-escalation study was undertaken to define the safety and pharmacokinetics (PK) of pemetrexed in patients with advanced solid malignancies and normal or impaired renal function. The principal study objectives were to characterize drug-related toxicities, define the maximum-tolerated dose, and to determine recommended doses in this patient population. Secondary objectives were to examine the effects of renal dysfunction on pemetrexed plasma and urine PK, and to evaluate the antitumor activity of pemetrexed in these patients.
Patient Eligibility Patients with advanced solid malignancies for whom standard treatment options did not exist were eligible for this study. Prior radiation therapy and/or chemotherapy had to be completed at least 30 days before study entry (6 weeks for nitrosourea or mitomycin). Other eligibility criteria included age  18 years; an Eastern Cooperative Oncology Group performance status  2; estimated life expectancy 12 weeks; adequate hematopoietic function (absolute neutrophil count 1,500/µL, platelet count 100,000/µL, and hemoglobin 9 g/dL); sufficient hepatic function (total bilirubin 1.5x the upper limit of normal [ULN], AST and ALT 3.0x ULN [AST or ALT 5x ULN if caused by liver metastasis]); and measurable or assessable disease. Exclusion criteria included any of the following: symptomatic or active brain metastasis; serious concomitant systemic disorders incompatible with the study; clinically significant pleural or peritoneal effusion; serum albumin less than 2.0 g/dL; body-surface area more than 3 m2; requirement for renal dialysis; or an inability to take folic acid or vitamin B12 supplementation. The use of aspirin or other nonsteroidal anti-inflammatory agents was not permitted from 2 days before (5 days for longer-acting agents) until 2 days after pemetrexed treatment. Written informed consent was obtained according to federal and local institutional guidelines. The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the applicable guidelines on good clinical practice.
Study Design
Only the 99mTc-DTPA-measured GFR was used to stratify patients into treatment groups. Group 1, consisting of patients with a GFR Starting doses were based on renal-function stratification. Dose escalations in new patients were conducted independently within each treatment group, with final pemetrexed doses not to exceed 600 mg/m2 in any group. Three patients were treated at the initial dose level within each treatment group, and if no cycle-1 DLTs were observed, three additional patients were treated at the next dose level. If one of three initial patients experienced a DLT at any given dose level, then three additional patients were treated at that same dose. If a DLT occurred in at least two patients at any dose level, then dose escalation was halted, and the next three patients enrolled onto that treatment group were treated at the next lower dose level. In treatment groups 2, 3, and 4, the first patient treated at any new dose level was observed for 3 weeks before two additional patients could receive the same dose. The maximum-tolerated dose and the recommended treatment dose for each treatment group were defined as the highest dose level at which less than two of six patients experienced DLT in cycle 1. More than six patients could be treated at the recommended dose level in each treatment group to obtain additional information about the tolerability of the dose. DLT was defined as any of the following occurring during cycle 1: grade 4 neutropenia lasting more than 5 days or associated with fever or infection; grade 4 thrombocytopenia; any grade 3 or 4 nonhematologic toxicity except for alopecia, suboptimally treated nausea, vomiting, or diarrhea; and unresolved drug-related toxicity delaying re-treatment more than 2 weeks. Toxicity was graded before every cycle according to the National Cancer Institute Common Toxicity Criteria, version 1.0.
Drug Formulation and Administration During the study, results from a multivariate regression analysis became available and indicated that an elevated baseline homocysteine level (consistent with subclinical folate deficiency) was highly correlated with more severe pemetrexed toxicities.25 To reduce the more severe drug-induced toxic effects, the protocol was amended to include supplementation of patients with folic acid and vitamin B12. Patients enrolled after December 1999 were instructed to take folic acid 350 to 600 µg or equivalent orally daily and received vitamin B12 1,000 µg intramuscularly every 9 weeks, both beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing until the patient completed pemetrexed therapy. Supportive therapies included high-dose loperamide for diarrhea, and prochlorperazine and/or 5-hydroxytryptamine-3 receptor antagonists for nausea and vomiting. No other anticancer therapies or experimental medications were permitted during the study.
Baseline and Treatment Assessments
Pharmacokinetic Sampling and Bioanalytic Methodology
Pharmacokinetic and Pharmacodynamic Analyses
Patient Demographics and Clinical Characteristics Between May 1998 and November 2000, 47 patients were enrolled and treated with at least one cycle of pemetrexed (Tables 1 and 2). Of these, 13 patients were supplemented with folic acid and vitamin B12, whereas 34 patients received no vitamin supplementation.
The target patient accrual goals were met in group 1 (GFR 60 mL/min) and group 2 (GFR 40 to 59 mL/min). However, patient accrual in group 4 (GFR < 20 mL/min) and subgroup 3B (GFR 20 to 29 mL/min) was halted after the only patient treated in group 4 died as a result of severe pemetrexed-related toxicities. Although accrual remained open in subgroup 3A (GFR 30 to 39 mL/min), no patients were enrolled. The mean GFR in groups 1A, 1B, and 2 was 112 mL/min (range, 80 to 151 mL/min), 67.2 mL/min (range, 60.7 to 75 mL/min), and 50.8 mL/min (range, 41 to 59 mL/min), respectively, whereas the group 4 patient had a GFR of 19 mL/min.
DLTs
In group 1A, no DLTs were observed in the first three patients treated with 500 mg/m2 of pemetrexed. At 600 mg/m2, one patient (nonsupplemented with folic acid and vitamin B12) developed grade 3 neuroconstipation. Although it was unlikely that this toxicity was related to pemetrexed administration, the group was expanded to include four additional patients. Because one of these patients (nonsupplemented) developed grade 4 febrile neutropenia in cycle 1, eight additional patients were treated at 500 mg/m2; two of these eight patients developed DLTs (one grade 4 febrile neutropenia in a vitamin-supplemented patient and one grade 3 fatigue in a nonsupplemented patient). Thus, two of 11 patients treated at 500 mg/m2 and two of seven patients treated at 600 mg/m2 had DLTs. Therefore, 600 mg/m2 was the recommended pemetrexed dose for patients with a GFR 80 mL/min. In group 1B, one of eight patients (nonsupplemented) treated with 500 mg/m2 and one of five patients (vitamin supplemented) treated at 600 mg/m2 experienced DLTs (grade 4 febrile neutropenia concurrent with grade 4 thrombocytopenia and grade 3 fatigue, and grade 4 febrile neutropenia, respectively). Because fewer than six total patients were treated at the highest dose level in this group, 500 mg/m2 was the recommended pemetrexed dose for patients with a GFR of 60 to 79 mL/min. In group 2, one of six patients (nonsupplemented) treated with 400 mg/m2 experienced dose-limiting grade 3 fatigue. Because one of the first three patients treated with 500 mg/m2 experienced treatment-related grade 4 neutropenia (in cycle 2), six additional patients were treated at this dose level. None of these six patients experienced DLTs; therefore, 500 mg/m2 was the recommended pemetrexed dose for patients with a GFR of 40 to 59 mL/min. The only patient enrolled onto group 4 (with a GFR of 19 mL/min) treated with 150 mg/m2 developed DLTs of grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 stomatitis, and grade 3 fatigue, and he died on day 20 of cycle 1. The patient was a 79-year-old male with hormone-refractory metastatic adenocarcinoma of the prostate. He did not have clinical evidence of folate deficiency and was enrolled before amendment of the protocol to include folic acid and vitamin B12 supplementation. As a result, group 4 (GFR < 20 mL/min) and subgroup 3B (GFR 20 to 29 mL/min) were closed to further accrual. Accrual to subgroup 3A (GFR 30 to 39 mL/min) remained open, but no patients were enrolled onto this group. A second on-study death occurred in a 67-year-old male with NSCLC assigned to group 1A who was treated with 600 mg/m2 of pemetrexed without vitamin supplementation. This patient developed an acute myocardial infarction during cycle 3; however, this death was considered unrelated to the study drug.
Hematologic Toxicity
Nonhematologic Toxicities Grade 3 and 4 nonhematologic toxicities were infrequent and varied in distribution across treatment groups and dose levels. One episode of grade 4 mucositis occurred in the group 4 patient who experienced fatal drug-related toxicity. Four patients developed serious skin toxicities that were highly variable in clinical presentation, including a lower-extremity cellulitis, a generalized maculopapular rash, Schamberg's purpura, and a leukocytoclastic vasculitis. The most frequently reported grade 3 toxicities were neuromotor weakness or fatigue (five patients total, two with vitamin supplementation) and diarrhea (four patients total, one with vitamin supplementation). Other observed grade 3 clinical toxicities included nausea (three patients), pulmonary (one patient), neurocortical (one patient), and constipation (one patient). The distribution of these events did not correlate with renal function (six patients in group 1A, five patients in group 1B, three patients in group 2, and one patient in group 4). GI adverse effects were typically mild, and nausea/vomiting and diarrhea were generally responsive to symptomatic therapies. No evidence of cumulative toxicity was seen. Dose reductions were required in 7.6%, 6.3%, and 3.7% of the 167 administered cycles in groups 1A, 1B, and 2, respectively.
PK and Pharmacodynamic Evaluation
Pemetrexed CLp decreased with declining renal function (Tables 5 and 6). Regression analysis of the log-transformed clearance values showed a strong correlation between CLp and the 99mTc-DTPA-measured GFR (slope = 0.888; 95% CI, 0.730 to 1.05; r2 = 0.736; P < .0001; Fig 2A). Consistent with earlier PK studies, unchanged pemetrexed was the predominant drug species excreted in the urine. Cumulative renal excretion of pemetrexed reached a plateau within 12 to 24 hours after drug administration, except for the one group 4 patient with severe renal impairment who demonstrated delayed renal drug excretion (Fig 3). Pemetrexed CLr decreased with declining renal function (Tables 5 and 6). Regression analysis of the log-transformed clearance values showed CLr to correlate with 99mTc-DTPA-measured GFR (slope = 1.52; 95% CI, 1.01 to 2.02; r2 = 0.451; P < .0001; Fig 2B).
Estimates of CLp and CLr by renal function, based on the regression analyses between CLp and GFR versus CLr and GFR, are summarized in Table 6. Notably, CLr as a proportion of total clearance (ie, CLr/CLp) decreased with decreasing renal function. In addition, clearance due to filtration (unbound fraction x GFR28) as a proportion of overall CLr (ie, [unbound fraction x GFR]/CLr) increased as renal function decreased.
The PK results have also been evaluated retrospectively relative to body surface area (BSA) –indexed GFR (Table 7). Fifteen patients were reclassified into different renal function groups based on BSA indexing of GFR: four patients from group 1A to group 1B; one patient from group 1A to group 2; seven patients from group 1B to group 2; two patients from group 2 to group 3A; and one patient from group 1B to 1A. The reanalysis (Table 7) yielded similar results to those obtained from the initial evaluation based on unadjusted GFR (Table 5). Moreover, the regressions of log-transformed pemetrexed CLp and CLr versus BSA-indexed GFR showed strong correlations (slope = 0.841; 95% CI, 0.645 to 1.04; r2 = 0.619; P < .0001 for CLp, and slope = 1.39; 95% CI, 0.831 to 1.96; r2 = 0.356; P < .0001 for CLr) that were consistent with the original regressions based on unadjusted GFR. Furthermore, reanalysis of the clinical safety data demonstrated the clinical tolerability of pemetrexed for patients with BSA-indexed GFR
The pharmacodynamic relationships between pemetrexed exposure as estimated by AUC0-  and the decrease in blood counts (WBC count, absolute neutrophil count, and platelet counts) were explored using a maximal effect model. However, no consistent relationships were identified that correlated any PK parameter and drug-induced myelosuppression.
Antitumor Efficacy
Comparison of Renal Function Measures
Single-agent pemetrexed therapy administered as a 10-minute infusion every 3 weeks at doses 500 mg/m2 with vitamin supplementation was well tolerated in patients in group 1A (GFR 80 mL/min), group 1B (GFR 60 to 79 mL/min), and in group 2 (GFR 40 to 59 mL/min). As expected, the major DLTs were hematologic, with four patients developing febrile neutropenia and one patient experiencing prolonged neutropenia (> 5 days). Most pemetrexed-induced toxicities were well tolerated and manageable. Hematologic and nonhematologic toxicities were mild to moderate and were consistent with those reported in other pemetrexed studies.20 These included neutropenia, thrombocytopenia, skin rash, fatigue, diarrhea, and mucositis. Pemetrexed-related toxicities were observed throughout all treatment groups, and the incidence and severity did not correlate with the degree of renal dysfunction in patients with a GFR 40 mL/min. No evidence of any pemetrexed cumulative toxicities or nephrotoxicity was observed. Thus, 500 mg/m2 of pemetrexed with vitamin supplementation can be administered safely to patients with a GFR of 40 to 79 mL/min, whereas patients with a GFR 80 mL/min can tolerate a higher pemetrexed dose of 600 mg/m2. Because the only patient in group 4 (GFR 19 mL/min) died as a result of drug-related toxicities, enrollment was completed only for patients with a GFR 40 mL/min. On the basis of these results, dosing guidelines cannot be recommended for patients with a GFR less than 40 mL/min. This study showed that drug clearance was substantially reduced in patients with renal impairment. Pemetrexed CLp values for renally impaired patients in this study were consistent with those for 80 renally impaired patients (CrCL < 80 mL/min) enrolled onto phase II and III studies.22 In this study, pemetrexed CLp varied over a wide range and correlated with the measured GFR (r2 = 0.736). As the GFR decreased from 100 to 40 mL/min, pemetrexed CLp decreased by 56%. As a consequence, pemetrexed systemic exposure increased in patients with impaired renal function. Similar pharmacokinetic characteristics have been reported for methotrexate32 and raltitrexed.33
For pemetrexed, however, the increase in systemic exposure was not associated with an increase in drug-related DLTs for vitamin-supplemented patients with GFRs Pemetrexed is eliminated by both tubular secretion and glomerular filtration; however, the relative contribution of these mechanisms to pemetrexed CLr has not been characterized precisely. This study showed that net tubular secretion is the predominant mechanism of pemetrexed CLr for patients with normal renal function (for example, GFR 100 mL/min). Furthermore, the study demonstrated that as renal function decreases, the relative contribution of net tubular secretion to pemetrexed elimination decreases and glomerular filtration becomes the primary mechanism of pemetrexed CLr. Tubular secretion typically accounts for an increasing proportion of CLr as renal function declines, which is the opposite of that observed in this study. A number of potential explanations are consistent with these findings. If tubular reabsorption of pemetrexed is substantially increased in patients with diminished renal function, net tubular secretion would decrease. Given that endogenous organic acids are known to accumulate with declining renal function,38 these acids might accumulate sufficiently to compete with pemetrexed for tubular secretion in patients with diminished renal function such that glomerular filtration becomes the primary mechanism of renal elimination. Although the precise transport system(s) responsible for pemetrexed tubular handling is not known, it is known that expression of the kidney-specific organic anion transporters K1 and K2 are decreased in kidney disease in partially nephrectomized laboratory animals.39 It is possible that reduction in these transporters might account for decreased tubular secretion of pemetrexed in our study. Finally, although the underlying cause for renal insufficiency was not documented in this study, the decrease in net renal tubular secretion with decreasing renal function is also consistent with chronic tubulointerstitial diseases such as interstitial nephritis or nephrotoxic injury. The current study also compared several measures of renal function. Study stratification was based on the 99mTc-DTPA-measured GFR, which was anticipated to be the most accurate method of quantifying renal function. However, because measured GFR is not easily implemented as a routine clinical test, prediction equations are often used to estimate GFR. Although the CrCLCG,std equation is widely used, and is the recommended method for assessing renal function for drug dosing in US Food and Drug Administration guidances,40 its predictive performance, especially in specific subpopulations, continues to be a topic of research and debate.29,30,41-43 Specifically, CrCLCG,std has been shown to be less accurate in emaciated, highly muscular, or obese patients.28 Early clinical trials of pemetrexed used CrCLCG,LBM as the basis for patient enrollment because cancer patients tend to have a greater proportion of lean body mass and this formula addresses this issue; however, CrCLCG,LBM is a much more complex and cumbersome calculation than CrCLCG,std. In our trial, the CrCLCG,std formula provided a reasonable approximation of the measured GFR, and demonstrated that it is not necessary to use the CrCLCG,LBM formula in this patient population. The CrCLCG,std formula resulted in a slight overestimation (MPE = 6.4%) of GFR in the current study, whereas previous reports have indicated that CrCLCG,std may underestimate GFR in cancer patients with normal or mildly impaired renal function.29,44,45 The reason for this disparity is unclear, but may be related partially to different methods for determining serum creatinine. With numerous methods currently in use for the measurement of serum creatinine,46 differences in measurement methodology and lack of calibration across clinical laboratories have been identified as critical limitations to the estimation of GFR by equation,29,47-49 and these factors are estimated to account for prediction errors as high as 20%.47 In our study, creatinine was measured using a compensated rate-blanked creatinine assay (modified Jaffe reaction), which eliminates the overestimation of creatinine that occurs in the unmodified Jaffe reaction.
In this study, patients were stratified by CrCL uncorrected for BSA; however, pemetrexed dosing recommendations are made on BSA-based calculations. Although it is now increasingly accepted to use a GFR adjusted for BSA as the measure of renal function when drug dosing is based on BSA,50,51 this was not yet a standard practice when this study was planned and conducted. Therefore, for this report, we evaluated the results retrospectively relative to BSA-adjusted GFR. However, these changes did not have an impact on the overall conclusions of the study (Table 7). One possible explanation for the consistency in results between the analysis based on unadjusted GFR and that based on BSA-indexed GFR is the relatively poor correlation between GFR and BSA (r2 = 0.0654; P = .079; slope = 32.2; 95% CI, –3.91 to 68.4) for patients enrolled onto this study, which has also been demonstrated in previous studies.52,53 Second, although pemetrexed is dosed based on BSA as a consequence of clinical development being initiated in the timeframe when such practice was routine, it has now been established that pemetrexed CL is correlated with CrCL, that BSA offers no further explanatory value relative to pemetrexed CL,54 and that toxicity correlates with overall exposure (and therefore, CL).55,56 In addition, the therapeutic index for pemetrexed when administered with vitamin supplementation is considerably enhanced,57 which further explains why the indexing of GFR to BSA does not impact conclusions relative to clinical toxicities for this study. Finally, given that the large majority of reclassifications (14 of 15) resulted in BSA-indexed GFRs that were lower than the absolute GFRs, this reanalysis supports the recommendation of no dose adjustment for patients with a GFR
On a cautionary note, although our current study indicates that dose adjustments are not necessary for vitamin-supplemented patients with renal impairment (GFR
In conclusion, patients with a GFR
Although all authors completed the disclosure declaration, the following authors 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank Patti Moore and Noelle Gasco for writing and editorial assistance; Diana Kelley for technical support; Sheila Dropcho, Karen Fife, Linda Battiato, and the staffs of the Cancer Therapy Research Center and the Indiana University Medical Center, for assistance with study conduct.
Supported by Eli Lilly and Company. Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001, and the 27th European Society for Medical Oncology Congress, Nice, France, October 18-22, 2002. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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