title: Pralatrexate with vitamin supplementation in patients with previously treated, advanced non-small cell lung cancer: safety and efficacy in a phase 1 trial.
abstract: BACKGROUND
  Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities.
  
  
  METHODS
  Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response.
  
  
  RESULTS
  Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2).
  
  
  CONCLUSIONS
  Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York City, New York, USA. azzolic@mskcc.org
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.forename: Jyoti D
authors.initials: JD
authors.lastname: Patel
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.forename: Leonard
authors.initials: L
authors.lastname: James
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Michelle
authors.initials: M
authors.lastname: Ginsberg
authors.forename: Sara
authors.initials: S
authors.lastname: Subzwari
authors.forename: Leslie
authors.initials: L
authors.lastname: Tyson
authors.forename: Megan
authors.initials: M
authors.lastname: Dunne
authors.forename: Jennifer
authors.initials: J
authors.lastname: May
authors.forename: Martha
authors.initials: M
authors.lastname: Huntington
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.forename: F M
authors.initials: FM
authors.lastname: Sirotnak
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000368:Aged; D000630:Aminopterin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D014018:Tissue Distribution; D014805:Vitamin B 12 / Q000008:administration & dosage; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D014803:Vitamin B Complex; D005492:Folic Acid; D000630:Aminopterin; D014805:Vitamin B 12