title: Phase 1 study evaluating the safety and pharmacokinetics of pralatrexate in relapsed/refractory advanced solid tumors and lymphoma patients with mild, moderate, and severe renal impairment.
abstract: OBJECTIVE
  Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma. It has not been formally tested in patients with renal impairment. This study evaluated the pharmacokinetic (PK) profile of pralatrexate in patients with renal impairment and with relapsed/refractory advanced solid tumors and lymphoma.
  
  
  METHODS
  This was an open-label, nonrandomized, phase 1 study. Eligible patients received pralatrexate administered as an IV push over 3-5 min once weekly for 6 weeks in 7-week cycles until progressive disease or intolerable toxicity. Four cohorts of 6 patients were planned for a total of 24 patients. Patients with normal renal function (Cohort A), mild (Cohort B), and moderate renal impairment (Cohort C) received 30 mg/m2pralatrexate once weekly for 6 weeks in 7-week cycles, and patients with severe renal impairment (Cohort D) were to be administered 20 mg/m2once weekly for 6 weeks. Plasma and urine samples were collected at pre-specified time points to determine the PK profile of pralatrexate in each treatment cohort. Patients were followed for safety and tolerability.
  
  
  RESULTS
  A total of 29 patients were enrolled and 27 patients (14 male) received at least 1 dose of pralatrexate. Because of a qualifying toxicity in Cohort C, the starting dose for Cohort D was reduced to 15 mg/m2. Chronic renal impairment led to a decrease in renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Pralatrexate exposure in Cohort D (15 mg/m2) was similar to the exposure in other cohorts (30 mg/m2). No apparent difference in toxicity between the four treatment cohorts was observed, except for an increase in cytopenias in patients with severe renal impairment.
  
  
  CONCLUSIONS
  Pralatrexate exposure, at a dose of 30 mg/m2, in patients with mild or moderate renal impairment was similar to the exposure in patients with normal renal function. For patients with severe renal impairment only, a pralatrexate dose of 15 mg/m2is recommended.
authors.affiliation: Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California, 1441 Eastlake Ave, NOR 3465, MC 9172, Los Angeles, CA, 90033, USA. kevin.kelly@med.usc.edu.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.affiliation: Gabrail Cancer Center Research, 4875 Higbee Ave. NW, Canton, OH, 44718, USA.
authors.forename: Nashat
authors.initials: N
authors.lastname: Gabrail
authors.affiliation: UT Health Science Center, Cancer Therapy and Research Center, 7979 Wurzbach Road, San Antonio, TX, 78229, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Weitman
authors.affiliation: UT Health Science Center, Cancer Therapy and Research Center, 7979 Wurzbach Road, San Antonio, TX, 78229, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.affiliation: Greenville Hospital Systems Institute for Translational Oncology Research, 900 West Faris Rd CTC, 3rd Floor, CRU, Greenville, SC, 29605, USA.
authors.forename: William
authors.initials: W
authors.lastname: Edenfield
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 N 12th Street, P.O. Box 980533, Richmond, VA, 23298-0533, USA.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Venitz
authors.affiliation: Spectrum Pharmaceuticals, Inc., 157 Technology Dr., Irvine, CA, 92618, USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Reddy
authors.affiliation: Spectrum Pharmaceuticals, Inc., 157 Technology Dr., Irvine, CA, 92618, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Yang
authors.affiliation: Spectrum Pharmaceuticals, Inc., 157 Technology Dr., Irvine, CA, 92618, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hasal
authors.affiliation: Washington University School of Medicine, 660 Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
mesh_terms: D000328:Adult; D000368:Aged; D000630:Aminopterin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D023381:Endpoint Determination; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism; D007677:Kidney Function Tests; D008223:Lymphoma / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D051437:Renal Insufficiency / Q000150:complications* / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D000630:Aminopterin
keywords: Lymphoma; Pharmacokinetics; Pralatrexate; Renal