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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Institute for Drug Development at the Cancer Therapy and Research Center and University of Texas Health Science Center, San Antonio, Texas and 2 Eli Lilly and Company, Indianapolis, Indiana
Requests for reprints: Chris H. Takimoto, Institute for Drug Development, Cancer Therapy and Research Center, Alice P. McDermott Building, 14960 Omicron Drive, San Antonio, TX 78245-3217. Phone: 210-677-3800; Fax: 210-677-0058; E-mail: ctakimot{at}idd.org.
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Abstract |
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Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1.
Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation.
Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.
(2), and once in the cell, it is polyglutaminated by folypoly-
-glutamate synthase. Pemetrexed polyglutamation prolongs its intracellular retention and enhances its interaction with the target enzymes (3). In addition to specifically inhibiting thymidylate synthase (4, 5), pemetrexed is also a potent inhibitor of the key folate-dependent enzymes dihydrofolate reductase and glycinamide ribonucleotide formyl transferase (1). The multiple mechanisms of action of pemetrexed may explain its greater potency and broader spectrum of antitumor activity in preclinical studies compared with other antimetabolites such as 5-fluorouracil, methotrexate, or raltitrexed (1, 6). In clinical studies, antitumor activity has been observed in patients with thoracic malignancies (malignant mesothelioma and non–small-cell lung cancer) as well as colorectal, pancreatic, bladder, head and neck, cervical, gastric, and breast carcinomas (7, 8). In the United States, pemetrexed is approved for use in combination with cisplatin for treating chemotherapy-naive patients with malignant mesothelioma and as a single agent for second-line therapy in advanced non–small-cell lung cancer patients (9–11).
Pemetrexed is principally eliminated by renal excretion, with 70% to 90% of the administered drug recovered in the urine within 24 h. It is rapidly eliminated, with a total systemic clearance of 91.8 mL/min and a half-life of 3.5 h in patients with normal renal function (creatinine clearance of 90 mL/min). Pharmacokinetic evaluations have shown that pemetrexed exhibits dose-proportional pharmacokinetics over a broad dose range (0.2-838 mg/m2; ref. 11).
A study of pemetrexed in patients with advanced solid malignancies and impaired renal function (creatinine clearance of 40-79 mL/min) found that patients supplemented with folate and vitamin B12 tolerated a dose of 500 mg/m2 every 3 weeks (12). In addition, a study of pemetrexed in advanced cancer patients with creatinine clearance 
60 mL/min showed that pemetrexed generated minimal myelosuppression and was well tolerated at a dose of 500 mg/m2 with vitamin supplementation when coadministered with aspirin (325 mg every 6 h) or ibuprofen (400 mg every 6 h; ref. 13).
Preclinical data suggest that dietary folate stores have a profound effect on the toxicity and antitumor activity of antifolates. Low-folate diets increased the toxicity of lometrexol, an antifolate glycinamide ribonucleotide formyl transferase inhibitor (14). Mice fed a folate-deficient diet had a 1,000-fold increase in sensitivity to the lethal effects of lometrexol compared with mice fed a standard diet. Changing to a standard or slightly enhanced folate-supplemented diet allowed larger doses of lometrexol to be administered with less toxicity and greater antitumor activity. However, excessive high-dose folate replacement-negated antitumor effects of lometrexol (14). In clinical studies, oral folic acid supplementation increased the tolerability of lometrexol doses that were previously intolerable when administered without folic acid (15).
The initial clinical development of pemetrexed did not include mandatory folate supplementation. However, in 2002, a multivariate regression analysis showed that patients with an elevated baseline homocysteine level, consistent with subclinical folate deficiency, were significantly more prone to experiencing severe pemetrexed toxicities (16). To reduce the more severe drug-induced toxic effects, most protocols involving pemetrexed were amended to include supplementation of patients with nutritional doses of folic acid and vitamin B12.
Because the recommended dose of pemetrexed was established previously in clinical trials that did not include mandatory folate supplementation, the current study was initiated to evaluate the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed. The primary objective of this study was to determine the tolerable dose of pemetrexed when administered with intermittent oral high-dose (5 mg daily for 5 days) folic acid supplementation in lightly pretreated (LPT) and heavily pretreated (HPT) patients with locally advanced or metastatic cancer. Subsequently, the study was amended to examine how the degree of prior myelosuppressive therapy affected pemetrexed tolerability and to explore the effects of continuous daily administration of 350 to 600 µg folate in the form of standard multivitamins on the tolerability of pemetrexed. Secondary objectives included the determination of a well-tolerated phase II dose for future studies, the characterization of associated toxicities, documentation of antitumor activity, and assessment of plasma pharmacokinetics.
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Patients and Methods |
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100 x 109/L), hepatic function (bilirubin 
1.5 times the upper limit of normal, aspartate transaminase, or alanine transaminase 3.0 times normal, or an aspartate transaminase or alanine transaminase 5 times normal if due to malignant liver disease), and renal function (creatinine clearance 45 mL/min). Prior radiation (to <25% of total bone marrow) or chemotherapy was allowed, as long as it was completed 3 weeks before study entry (6 weeks for nitrosourea or mitomycin-C therapy), and patients had recovered from acute therapy-related toxicities. Patients with prior pelvic radiation were eligible only for the HPT cohort. Patients with leukemia, lymphoma, multiple myeloma, active brain metastases, prior treatment with pemetrexed, clinically significant effusions (pleural or peritoneal), or the inability to interrupt nonsteroidal anti-inflammatory drugs were ineligible for enrollment. The protocol was approved through institutional ethical review boards, and all patients provided written informed consent before treatment. The study was conducted in accordance with the ethical principles stated in the most recent version of the Declaration of Helsinki or the applicable guidelines on good clinical practice.
Study design. The study was conducted at the Institute for Drug Development at the Cancer Therapy and Research Center and the University of Texas Health Science Center, San Antonio, Texas and was originally designed as a single cohort, open-label, phase I, dose-finding trial of pemetrexed with intermittent high-dose folic acid (HDFA) supplementation in patients with locally advanced or metastatic cancer. However, the protocol was subsequently amended to add a second cohort of patients continuously supplemented with daily multivitamins (MVI) containing nutritional doses of folic acid. Further protocol amendments introduced the stratification of patients into LPT and HPT cohorts, ultimately resulting in four separate dose escalation cohorts (HDFA-HPT, HDFA-LPT, MVI-HPT, and MVI-LPT). LPT patients were those who received any of the following as prior treatment for cancer: no prior treatment, less than two courses of mitomycin-C, less than six courses of an alkylating agent, or less than four courses of carboplatin. HPT patients were those who previously received one or more of these treatments for their cancer or any radiotherapy to the pelvis. Patients were enrolled in the HDFA cohorts first; after enrollment in these cohorts was completed, enrollment proceeded in the MVI cohorts.
Treatment. Pemetrexed was administered on day 1 as a 10-min i.v. infusion of 600 to 1,400 mg/m2 every 3 weeks. Patients in the intermittent HDFA cohort were supplied with folic acid as 1-mg tablets from a single commercial source and were instructed to take five 1-mg tablets orally each day for 2 days before pemetrexed therapy, on the day of treatment, and for 2 days following treatment. Patients in the daily MVI cohort were supplied with multivitamins provided by the sponsor containing 350 to 600 µg folic acid, which they were to take daily, starting 7 days before the first dose of pemetrexed and continuing until the end of the study. Patient diaries were collected to monitor compliance with the treatment regimens. Separate supplementation with vitamin B12 was not included in either treatment regimen; however, the oral MVI preparations used in this study did contain vitamins B6 and B12.
Supportive therapy with granulocyte colony-stimulating factors was allowed only if patients developed dose-limiting neutropenia, or if an infection was documented while the patient was neutropenic. Granulocyte colony-stimulating factor support had to be discontinued at least 24 h before the initiation of the next cycle of pemetrexed therapy. Leucovorin administration was allowed for patients with grade 4 leukopenia, grade 4 myelosuppression lasting longer than 7 days, or grade 3 pemetrexed-induced mucositis. Leucovorin rescue consisted of 100 mg/m2 given i.v. once followed by a dose of 50 mg/m2 i.v. every 6 h for 8 days. Concomitant administration of leucovorin and granulocyte colony-stimulating factor was permitted. Prophylactic oral dexamethasone was not used in new patients; however, it was permitted for patients experiencing pemetrexed-associated grade >2 rash in previous cycles.
Dose adjustments for subsequent cycles of therapy were based on platelet and neutrophil nadirs from the preceding cycle of therapy, nonhematologic toxicities, and calculated creatinine clearance. The absolute neutrophil count (ANC) had to be 1.5 x 109/L; platelets had to be 100 x 109/L; and the creatinine clearance had to be >45 mL/min before the start of any cycle. Pemetrexed dose was reduced by 25% for an ANC <0.5 x 109/L for 5 days and platelets 50 x 109/L, by 50% for an ANC 0.5 x 109/L and platelets 25 to 49 x 109/L, and by 75% for an ANC <0.5 x 109/L for 5 days and platelets 25 to 49 x 109/L or any ANC and platelets <25 x109/L. Patients who failed to recover to appropriate neutrophil and platelet counts after a delay of more than 15 days were discontinued. In addition, for grade 3 nonhematologic toxicities (except for grade 3 transaminase elevations that returned to the baseline value, nausea and/or vomiting, and alopecia), treatment was delayed until resolution or return to the patient's baseline value. Upon recovery, if treatment was resumed, it was to be resumed at 75% of the initial dose. For grade 3 to 4 mucositis, the dose was reduced by 50%; patients who had recurrence of mucositis after two treatments at the reduced dose were discontinued.
Dose escalation. Dose-limiting toxicities (DLT) affecting dose escalation were defined as any of the following occurring during cycle 1: grade 4 neutropenia lasting 5 days; febrile neutropenia; grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding requiring platelet transfusion; any grade 3 or 4 nonhematologic toxicity except for alopecia, nausea, suboptimally treated vomiting, or isolated, reversible, grade 3 alanine transaminase or aspartate transaminase. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (version 1.0).
Three patients were treated at the initial dose level (600 mg/m2) within each cohort, and if no 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 up to three additional patients were treated at that same dose. If a DLT occurred in at least 2 of 6 (33%) patients at any dose level, then dose escalation was halted for unacceptable toxicity. Additional patients enrolled in that cohort were treated at the next lower dose level until a maximum of nine patients were treated at that level. If 33% of patients experienced a DLT at the dose level below that which halted dose escalation, then de-escalation to the next lower dose level was to occur, and expansion of up to nine patients was repeated. The highest dose level at which DLTs occurred in <33% of at least six patients was considered tolerable. Intrapatient dose escalation was not permitted. If any DLT occurred after cycle 1, the potential cumulative toxic effects were taken into account for the determination of the well-tolerated phase II dose of pemetrexed.
Baseline and treatment assessments. Medical histories, physical examinations, and performance status evaluations were done pretreatment and weekly. Laboratory evaluations included complete blood cell counts with differential counts, liver function tests, chemistries, and serum creatinine. Toxicities were rated using the Common Toxicity Criteria scale at the beginning of each cycle, starting with cycle 2. Before each treatment cycle, creatinine clearance was assessed, either calculated using the original weight-based Cockcroft and Gault formula (17) or measured via glomerular filtration rate using the appropriate radiolabeled method (51-CrEDTA or Tc99m-DTPA). Radiologic imaging studies for disease assessment were conducted pretreatment and before every other cycle at the discretion of the investigator. Tumor response was assessed using standardized bidimensional measurements according to the Eastern Cooperative Oncology Group criteria (18).
Pharmacokinetic sampling and bioanalytic methodology. For patients in the HDFA cohort, heparinized blood samples for pemetrexed measurement were collected during cycle 1 before dosing and at 0.17, 0.25, 0.5, 1, 2, 4, 6, 9, and 24 h after the start of the drug infusion. For patients in the MVI cohort, heparinized blood samples for pemetrexed measurement were collected during cycle 1 before dosing and at 0.17, 0.25, 0.5, 1, 2, 4, 8, 24, 48, and 72 h after the start of the drug infusion. Samples were analyzed for pemetrexed at Taylor Technology, Inc. (Princeton, NJ), using a validated liquid chromatography/electrospray ionization-tandem mass spectrometry method that generated a linear response over the concentration ranges of 10 to 2,000 ng/mL and 1,000 to 200,000 ng/mL (19).
Pharmacokinetic analyses. Pharmacokinetic analyses were done using a population pharmacokinetics approach in the nonlinear mixed-effect modeling program, NONMEM (version V) with PREDPP (version V), using first-order conditional estimation (FOCE) with interaction (20). A three-compartment model with constant rate input (i.v. infusion), and parameterized in terms of clearance (CL), central volume of distribution (V1), intercompartmental clearances (Q2 and Q3), and peripheral volumes of distribution (V2 and V3), incorporating between-patient variability with respect to CL, V1, and V2, and a proportional residual error term, was used to describe the pharmacokinetics of pemetrexed. The model included creatinine clearance as a covariate with respect to CL and body surface area as a covariate with respect to V1 and V2.
Pemetrexed pharmacokinetics in the current study was compared with previous results without vitamin supplementation (21). In addition, the influence of the type of vitamin supplementation (HDFA versus MVI) and the degree of prior myelosuppressive therapy (LPT versus HPT) were evaluated. Each of the comparisons was done by adding these factors to the pharmacostatistical model as covariates [P = TVP
I1 + TVP[1 – I1]
, in which P is the variable of interest (i.e., CL, V1, or V2), TVP is the typical value of the variable, I1 is a dichotomous indicator variable, and is the covariate effect]. Differences were evaluated based on the 90% confidence interval (90% CI) of , with 0.7 to 1.43 used as the criteria for lack of difference.
Dose proportionality was assessed by using NONMEM to evaluate dose independence of CL, V1, and V2 using a power model (P = TVPDß, in which P is the pharmacokinetic variable, TVP is the typical value of the variable, D is dose, and ß is the effect of dose as a covariate) in a manner analogous to the method of Smith et al. (22); 90% CIs of –0.32 to 0.32 (which correspond to a 90% CI for the ratio of the variable at the highest dose to that of the lowest dose being contained within the range of 0.7-1.43) were used as the criteria for dose independence of each variable over the entire range of doses administered in this study. A dose-independence ratio, which corresponds to the maximum dose ratio over which dose independence of model variables can be inferred and is analogous to the dose proportionality ratio in Smith's study, was calculated based on the 90% CI of ß.
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Results |
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Patient characteristics were similar in the two cohorts (Table 1 ). Colon cancer was the most common cancer type for patients enrolled in each of the four cohorts. Forty-eight of the 62 patients (77.4%) in the HDFA cohort and 18 of 43 (41.9%) patients in the MVI cohort were Caucasian. All patients in each cohort had prior surgery, and nearly all patients had prior chemotherapy (Table 1).
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The 43 patients in the MVI cohort completed 182 cycles of therapy: 20 HPT patients completed 82 cycles, with a median of 2 cycles (range, 1-15), and 23 LPT patients completed 100 cycles, with a median of 3 cycles (range, 1-17). There were no dose omissions in this cohort. There were seven dose reductions, occurring in 6 (14.0%: 0 HPT and 6 LPT patients) of 43 patients and 11 drug-related dose delays in nine patients. Reasons for dose reductions and delays included lobar pneumonia, bacterial sepsis, abdominal pain, strangulated abdominal hernia, increased serum creatinine, increased transaminases, lung infection, nausea, neutropenia, and upper respiratory tract infection.
DLTs. In the HDFA-HPT cohort, at the 600 mg/m2 dose, one of nine patients had a DLT (grade 4 thrombocytopenia, Table 2
). None of the three patients treated at the 700 mg/m2 dose had a DLT, and at the 800 mg/m2 dose, none of the first six patients experienced a DLT. After further dose escalation to 925 mg/m2, two of six patients had DLTs [febrile neutropenia and grade 4 thrombocytopenia (in one patient) and grade 4 neutropenia lasting 5 days (in one patient)], thereby halting further dose escalation, and three additional patients were treated at the 800 mg/m2 dose level. One of these additional patients experienced a DLT (febrile neutropenia). Because only one of nine patients experienced a DLT at 800 mg/m2, this dose level was recommended for subsequent phase II studies of pemetrexed in HDFA-HPT patients.
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5 days. The criteria for halting dose escalation were achieved at 1,200 mg/m2, and two additional patients were treated at 1,050 mg/m2, one of whom had a DLT of grade 4 neutropenia lasting 5 days. Thus, the well-tolerated dose for phase II evaluation in HDFA-LPT patients is 1,050 mg/m2.
In the MVI-HPT cohort, at the 600 mg/m2 dose, none of the three patients had a DLT. Two of 11 patients at the 800 mg/m2 dose had DLTs manifested as a grade 3 allergic reaction and grade 3 neutropenia with cellulitis, and two of six patients had DLTs at the 925 mg/m2 dose level consisting of febrile neutropenia and grade 4 neutropenia lasting 5 days. Dose escalation was halted at 925 mg/m2, and the well-tolerated phase II dose for the MVI-HPT cohort was 800 mg/m2.
In the MVI-LPT cohort, none of the 20 patients at the first four dose levels (600, 800, 925, and 1,050 mg/m2) had DLTs. At the 1,200 mg/m2 dose level, two of three patients experienced DLTs of grade 4 thrombocytopenia and grade 4 neutropenia lasting 5 days, thereby halting any further dose escalation. The well-tolerated dose for further phase II study in the MVI-LPT cohort was 1,050 mg/m2.
Hematologic toxicities. Non–dose-limiting hematologic toxicities were common, occurred in all treatment groups, and did not relate to the type of vitamin supplementation (HDFA versus MVI) or the pretreatment status (HPT versus LPT, Table 3 ). Neutropenia was the most common hematologic toxicity (Table 3). Grade 4 neutropenia occurred in 13 of 62 (21.0%) patients in the HDFA cohort and in 6 of 43 (14.0%) patients in the MVI cohort. Grade 4 thrombocytopenia was less common, occurring in 4 of 62 (6.5%) patients in the HDFA cohort and in 3 of 43 (7.0%) patients in the MVI cohort. Grade 4 anemia occurred in 1 of 43 (2.3%) patients in the MVI cohort only. Grade 3 neutropenia was observed in 16 of 62 (25.8%) patients in the HDFA cohort and in 17 of 43 patients (39.5%) in the MVI cohort. Grade 3 anemia occurred in 11 of 62 (17.7%) patients in the HDFA cohort and in 10 of 43 (23.3%) patients in the MVI cohort. Grade 3 thrombocytopenia occurred in 4 of 62 (6.5%) patients in the HDFA cohort and in 2 of 43 (4.7%) patients in the MVI cohort.
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In the HDFA cohort, 5 (8.1%) patients discontinued therapy for possible drug-related serious adverse events: hypoxia (n = 1), decreased creatinine clearance (n = 2), thrombocytopenia (n = 1), and decreased plasma creatinine levels (n = 1). In the MVI cohort, 7 (16.3%) patients discontinued due to decreased creatinine clearance (n = 1), cellulitis (n = 2), hypersensitivity (n = 1), malaise (n = 1), osteomyelitis (n = 1), and decreased performance status (n = 1). Three patients in the MVI cohort experienced sudden unexpected and reportable events (bilateral subdural hematoma, heparin-induced thrombocytopenia, and osteomyelitis). Two patients in the MVI cohort died during the study from progressive malignant disease and coronary artery disease that were not thought to be related to pemetrexed therapy.
Tumor response. All patients enrolled in the four cohorts were eligible for the evaluation of antitumor activity. One HPT patient in the HDFA cohort with cancer of unknown primary treated at 600 mg/m2 had a partial response, whereas 20 of 62 (32.3%) patients in the HDFA cohort (treated at doses of 600-1,400 mg/m2) had stable disease as their best response. In the MVI cohort, three patients had partial responses, two patients with mesothelioma (1 HPT and 1 LPT) treated at 800 mg/m2, and one LPT patient with head and neck cancer treated at 600 mg/m2, whereas 19 of 43 (44.2%) patients (treated at doses of 600-1,400 mg/m2) had stable disease as their best response.
Pharmacokinetic evaluation. Pemetrexed plasma concentration-time data from 99 patients were evaluable for the pharmacokinetic analysis (Table 4 ). Pharmacokinetic profiles for all patients followed a similar pattern of multiexponential decay. As illustrated in Fig. 1 , these data were consistent with those from an earlier study (21) in which patients did not receive vitamin supplementation. Pemetrexed clearance in this study did not significantly differ from the earlier study, with the ratio of the clearance values (this study with vitamin supplementation/earlier study without vitamin supplementation) equal to 0.980 (95% CI, 0.9092-1.057).
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There were no clinically relevant differences in pemetrexed pharmacokinetics in LPT versus HPT patients or in patients receiving intermittent HDFA versus daily nutritional-dose MVI supplementation (Fig. 2).
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Discussion |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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1 to 2 weeks before the first dose of pemetrexed and continuing until the completion of pemetrexed therapy. This prophylactic measure substantially enhanced the tolerability of pemetrexed (500 mg/m2) while preserving efficacy (9). In this study, administration of pemetrexed doses up to 800 mg/m2, a 60% increase over the approved dose of 500 mg/m2, as a 10-min infusion every 3 weeks to heavily pretreated advanced cancer patients was well tolerated when supplemented with either intermittent HDFA or continuously administered standard multivitamins containing nutritional doses of folic acid. As expected, the major DLTs were hematologic, primarily neutropenia and thrombocytopenia. Overall, most drug-related toxicities were mild to moderate and were consistent with those reported in other pemetrexed studies (8, 23). In general, the pemetrexed-induced toxicities in the HPT groups were well tolerated and manageable. For all HPT patients, irrespective of the type of vitamin supplementation, dose escalation was halted for drug-related toxicities at 925 mg/m2, and the well-tolerated phase II dose of pemetrexed in these patients was 800 mg/m2.
In contrast, lightly pretreated advanced cancer patients tolerated slightly higher doses of pemetrexed than the HPT groups. The LPT patients tolerated doses of pemetrexed up to 1,050 mg/m2 administered as a 10-min infusion every 3 weeks when accompanied by either intermittent HDFA or continuously administered standard multivitamins containing nutritional doses of folic acid. Thrombocytopenia and neutropenia precluded further dose escalation in the LPT patients. In the LPT groups, hematologic and nonhematologic toxicities were mild to moderate and were consistent with those reported in other pemetrexed studies (8, 23). In general, the toxicities in the LPT groups were well tolerated and manageable. Dose escalation for these groups, independent of the type of vitamin supplementation, was halted at 1,200 mg/m2, with the well-tolerated phase II dose of pemetrexed being 1,050 mg/m2.
Folate supplementation using intermittent high doses or continuous nutritional doses of folic acid clearly reduced the clinical toxicities associated with pemetrexed and enabled higher doses of pemetrexed to be administered. However, the results of a recently completed breast cancer study showed the efficacy for a 900 mg/m2 dose to be similar to that for a 600 mg/m2 dose (24). Dose comparisons are also under way for non–small-cell lung cancer and ovarian cancer. The results of these studies will show whether there is additional gain in antitumor efficacy when pemetrexed is administered in combination with vitamin supplementation at doses higher doses than 500 mg/m2.
Although antitumor activity was not a primary objective of the current study, pemetrexed plus folic acid or multivitamin supplementation generated partial responses in four patients with mesothelioma (in two patients), unknown primary, and head and neck cancers. Three of the partial responders were in the MVI cohort, and one responder was in the HDFA cohort. The study design does not allow for an efficacy comparison of these two vitamin supplementation regimens. However, these data are encouraging and are consistent with preclinical studies that suggest that the coadministration of pemetrexed with folic acid can reduce systemic toxicities and preserve, or even enhance antitumor activity (25).
No differences in pemetrexed pharmacokinetics were observed in HPT patients versus LPT patients, or in patients supplemented with HDFA versus multivitamins containing nutritional doses of folic acid. For pemetrexed, areas under the curve were dose proportional over the entire range of pemetrexed doses tested, whereas Cmax values were dose proportional over any 2.1-fold dose range.
The observation that pemetrexed doses of 800 to 1050 mg/m2 are well tolerated when administered with vitamin supplementation is helpful in interpreting several recent clinical trials showing alterations in pemetrexed pharmacokinetics. For example, in a trial in patients with renal impairment, pemetrexed clearance was reduced in patients with decreased creatinine clearance (12). However, despite the resultant increase in area under the curve, standard doses of 500 mg/m2 of pemetrexed administered with vitamin supplementation were well tolerated in patients with glomerular filtration rates as low as 40 to 45 mL/min. Likewise, in a previously completed drug interaction study, ibuprofen coadministration altered drug clearance and increased pemetrexed areas under the curve by 20%, although clinical toxicities were not increased (13). In our current study, pemetrexed exposures 2-fold higher than those associated with standard dose pemetrexed regimens (500 mg/m2) were well tolerated when accompanied by vitamin supplementation. Thus, pemetrexed, when administered with vitamin supplementation, is tolerated over a relatively wide range of systemic exposures. Consequently, the current study suggests that the relatively modest increases in pemetrexed areas under the curve previously observed in patients taking ibuprofen are unlikely to be associated with an increase in clinical toxicity, even for patients with mild renal insufficiency (creatinine clearance, 60-79 mL/min).
In conclusion, the well-tolerated phase II dose for pemetrexed therapy accompanied by folic acid vitamin supplementation is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients. Pemetrexed is well tolerated, and the qualitative and quantitative toxicities of pemetrexed are similar and independent of the degree of prior myelosuppressive therapy or the type of vitamin supplementation (intermittent HDFA or continuous daily administration of multivitamins containing nutritional doses of folic acid). Vitamin supplementation results in significantly higher maximally tolerated doses of pemetrexed, and this regimen is active in patients with mesothelioma and other solid tumors. Further efficacy testing of pemetrexed at doses >500 mg/m2 administered with vitamin supplementation is warranted.
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9/27/06; revised 1/28/07; accepted 2/16/07.
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