Phase Iand Pharmacokinetic Studyof Pemetrexed with High-Dose Folic Acid Supplementationor Multivitamin Supplementationin Patients with LocallyAdvancedor Metastatic Cancer ChrisH.Takimoto, 1 LisaA.Hammond-Thelin, 1 JaneE.Latz, 2 LeonardoForero, 1 MuralidharBeeram, 1 BahramForouzesh, 1 JohanndeBono, 1 AnthonyW.Tolcher, 1 AmitaPatnaik, 1 PamelaMonroe, 1 LeslieWood, 1 KarenB.Schneck, 2 RomneeClark, 2 andEricK.Rowinsky 1 Abstract Purpose: ThisphaseIstudyevaluatedtheeffectoffolatesupplementationonthetoxicity, tolerability,andpharmacokineticsofpemetrexedinpatientswithlocallyadvancedormetastatic cancer.Italsoexaminedtwodifferenttypesofvitaminsupplementationandwhethertheextent ofpriormyelosuppressivetherapyaffectedpemetrexedtolerability. Patients and Methods: Patientsreceiveda10-mininfusionof600to14,00mg/m 2 pemetrexed every3weeks.Patientswerestratifiedintocohortsbypretreatmentstatus[lightlypretreated (LPT)orheavilypretreated(HPT)]andweresupplementedwithintermittenthigh-dosefolicacid (HDFA)orwithcontinuousdailymultivitamins(MVI)containingnutritionaldosesoffolicacid. Pemetrexedplasmapharmacokineticswereevaluatedforcycle1. Results: Sixty-twoHDFApatients(28HPTand34LPT)weretreatedwith204cyclesof pemetrexed,and43MVIpatients(20HPTand23LPT)weretreatedwith182cycles.Hema- tologicdose-limitingtoxicitiesincludedgrade4neutropenia(5of105patients),grade4throm- bocytopenia(4of105patients),andfebrileneutropenia(3of105patients).Nonhematologic toxicitiesincludedfatigue,vomiting,diarrhea,andnausea.Pemetrexeddosesof800and 1,050mg/m 2 werewelltoleratedwhenadministeredwithvitaminsupplementationtoHPT andLPTpatients,respectively.Therewerenoclinicallyrelevantdifferencesintoxicitiesorpeme- trexedpharmacokineticsforLPTversusHPTpatientsorforpatientsreceivingHDFAversusdaily MVIsupplementation. Conclusions: Thepemetrexeddosestoleratedinthisstudywithvitaminsupplementationwere significantlyhigherthanthosetoleratedinearlierstudieswithoutsupplementation,andtoxicities wereindependentofthetypeofvitaminsupplementationorpriormyelosuppressivetreatment. Therecommendeddoseofpemetrexedis1,050mg/m 2 inLPTpatientsand800mg/m 2 inHPT patients,irrespectiveofthetypeofvitaminsupplementation. Pemetrexed (LY231514/Alimta, Eli Lilly and Company) is a novel antifolate antimetabolite that inhibits a variety of en- zymesinvolvedinpurineandpyrimidinesynthesis.Unlikeother classic antifolates, it has a unique pyrrolopyrimidine nucleus and can inhibit multiple folate-dependent enzymes (1). Peme- trexed has a high affinity for binding to the folate receptor-a (2), and once in the cell, it is polyglutaminated by folypoly-g- glutamate synthase. Pemetrexed polyglutamation prolongs its intracellular retention and enhances its interaction with the target enzymes (3). In addition to specifically inhibiting thy- midylate 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 antimeta- bolites such as 5-fluorouracil, methotrexate, or raltitrexed (1, 6). In clinical studies, antitumor activity has been observed in patients with thoracic malignancies (malignant mesothelio- ma 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 chemother- apy-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 Cancer Therapy: Clinical Authors’Affiliations: 1 InstituteforDrugDevelopmentattheCancerTherapyand ResearchCenterandUniversityofTexasHealthScienceCenter,SanAntonio,Texas and 2 EliLillyandCompany,Indianapolis,Indiana Received9/27/06;revised1/28/07;accepted2/16/07. Grant support: EliLillyandCompany(Indianapolis,IN). Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.Thisarticlemustthereforebeherebymarked advertisement inaccordance with18U.S.C.Section1734solelytoindicatethisfact. Requests for reprints: ChrisH.Takimoto,InstituteforDrugDevelopment,Cancer TherapyandResearchCenter,AliceP.McDermottBuilding,14960OmicronDrive, SanAntonio,TX78245-3217.Phone:210-677-3800;Fax:210-677-0058;E-mail: ctakimot@idd.org. F 2007AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-06-2393 www.aacrjournals.org Clin Cancer Res 2007;13(9) May1, 2007 2675 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/13/9/2675/1973755/2675.pdf by guest on 14 June 2022