APhase1StudyofPralatrexateinCombinationwithPaclitaxelor DocetaxelinPatientswithAdvancedSolidTumors ChristopherG.Azzoli, 1 LeeM.Krug, 1 JorgeGomez, 1 VincentA.Miller, 1 MarkG.Kris, 1 MichelleS.Ginsberg, 2 RoxanneHenry, 5 Jessica Jones, 5 Leslie Tyson, 4 MeganDunne, 4 BarbaraPizzo, 4 AmyFarmer, 4 Ennapadam Venkatraman, 6 RobertSteffen, 7 andF.M.Sirotnak 3 Abstract Purpose: Pralatrexateisarationallydesignedantifolatewithgreaterpreclinicalantitumoractivity thanmethotrexate.Pralatrexatewassynergisticwithpaclitaxelandwithdocetaxelinmousexe- nograftexperiments.Thisphase1studywasdesignedtodeterminethemaximumtolerateddose andtoxicityofpralatrexatepluspaclitaxelordocetaxelinpatientswithadvancedcancer. Experimental Design: Pralatrexate was administeredi.v. every 2 weeks (days1and15) in a 4-weekcycle.Dependingonthetaxaneusedanddosebeingtested,thetaxanewasadministered ondays1and15;days2and16;ordays1,8,and15.Inthelatterpartofthestudy,patientsinthe docetaxel arm were treated with vitamin B 12 and folic acid supplementation to mitigate toxicity andallowpralatrexatedoseescalation. Results: For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested.Forpralatrexateplusdocetaxelplusvitaminsupplementation,pralatrexate120mg/m 2 plus docetaxel35mg/m 2 administeredonthesamedayeveryotherweekwasdefinedasthemaxi- mum tolerated dose and schedule, with dose-limiting toxicities at higher dose combinations in- cludingstomatitisandasthenia.Significantantitumoractivitywasobservedforthiscombination inpatientswithnon^small-celllungcancer. Conclusions: Pralatrexate(120mg/m 2 )plusdocetaxel(35mg/m 2 ) plus vitaminsupplementa- tioniswelltoleratedwithsignsofefficacyagainstnon^small-celllungcancerthatmeritphase2 testing. Compared with methotrexate, the 10-deazaaminoperin class of antifolate drugs show superior intracellular transport via the one-carbon, reduced folate carrier (RFC-1) and increased accumulation within cells by enhanced polyglutamylation (1–3). As a result, 10-deazaaminoperins have greater cytotox- icity than methotrexate against a variety of human cancers in xenograft experiments. The most potent 10-deazaaminopterin is pralatrexate (10- propargyl-10-deazaaminopterin; Fig. 1; refs. 4, 5). Pralatrexate is the most efficient substrate for RFC-1 and the most effective substrate for polyglutamylation by the enzyme folylpolygluta- mate synthetase compared with aminopterin, methotrexate, and edatrexate (2). In laboratory studies, pralatrexate was superior to edatrexate with 3- to 4-fold greater growth inhi- bition against a series of human non–small-cell lung cancer (NSCLC) cell lines (LX-1 and A549) in mouse xenograft experi- ments (4). A phase 1 trial of pralatrexate in patients with advanced cancer found stomatitis to be dose limiting, with a maximum tolerated dose (MTD) of 30 mg/m 2 when delivered weekly and 170 mg/m 2 when delivered every 2 weeks (6). Other observed toxicities included transaminase elevation, rash, pulmonary infiltrates, conjunctivitis, and epistaxis. No significant hemato- logic toxicities were noted. Pharmacokinetic analysis from the phase 1 trial revealed a mean area under the curve of 20.6 Amol h and a mean terminal half-life of 8 h at the 150 mg/m 2 dose. A phase 2 clinical trial of single-agent pralatrexate (135-150 mg/m 2 every 2 weeks) in a total of 39 patients with previously treated advanced NSCLC showed a radiologic response rate of 10% (95% confidence interval, 3-25%) and median survival time of 13.5 months (7). Two (5%) patients experienced grade 4 stomatitis and 6 (15%) had grade 3. No clinically significant myelosuppression was observed. The 10-deazaaminopterins show schedule-dependent syner- gy when combined with taxanes in mouse xenograft experi- ments. Pralatrexate has shown antitumor synergy with both paclitaxel and docetaxel in nude mice transplanted with the LX-1 tumor. 8 Pralatrexate showed synergy with each taxane 8 F.M.Sirotnak,unpublisheddata. Cancer Therapy: Clinical Authors’Affiliations: 1 Thoracic Oncology Service, Divisionof SolidTumor Oncology,DepartmentofMedicine; 2 DepartmentofRadiology, 3 Sloan-Kettering Institute, 4 DepartmentofNursing, 5 ClinicalTrialsOffice,and 6 Biostatistics,Memorial Sloan-KetteringCancerCenter,WeillMedicalCollege ofCornell University, New York,NewYork;and 7 AllosTherapeutics,Inc., Westminster,Colorado Received8/30/06;revised12/18/06;accepted1/29/07. Requestsforreprints: ChristopherG.Azzoli,ThoracicOncologyService,Division of SolidTumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center,1275 York Avenue, NewYork, NY10021. Phone: 212-832-2834; Fax:1-212-794-4357;E-mail:azzolic@mskcc.org. F 2007AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-06-1754 www.aacrjournals.org ClinCancerRes2007;13(9)May1,2007 2692