Kevin R Kelly1, Nashat Gabrail2, Steven Weitman3, John Sarantopoulos3, Anthony J Olszanski4, William Edenfield5, Jurgen Venitz6, Guru Reddy7, Allen Yang7, Steven J Hasal7, A Craig Lockhart8. 1. 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. 2. Gabrail Cancer Center Research, 4875 Higbee Ave. NW, Canton, OH, 44718, USA. 3. UT Health Science Center, Cancer Therapy and Research Center, 7979 Wurzbach Road, San Antonio, TX, 78229, USA. 4. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA. 5. Greenville Hospital Systems Institute for Translational Oncology Research, 900 West Faris Rd CTC, 3rd Floor, CRU, Greenville, SC, 29605, USA. 6. Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 N 12th Street, P.O. Box 980533, Richmond, VA, 23298-0533, USA. 7. Spectrum Pharmaceuticals, Inc., 157 Technology Dr., Irvine, CA, 92618, USA. 8. Washington University School of Medicine, 660 Euclid Avenue, St. Louis, MO, 63110, USA.
Abstract
PURPOSE: 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/m2 pralatrexate once weekly for 6 weeks in 7-week cycles, and patients with severe renal impairment (Cohort D) were to be administered 20 mg/m2 once 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. CONCLUSION: 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/m2 is recommended.
PURPOSE: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/m2 pralatrexate once weekly for 6 weeks in 7-week cycles, and patients with severe renal impairment (Cohort D) were to be administered 20 mg/m2 once 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. CONCLUSION: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/m2 is recommended.
Authors: L M Krug; K K Ng; M G Kris; V A Miller; W Tong; R T Heelan; L Leon; D Leung; J Kelly; S C Grant; F M Sirotnak Journal: Clin Cancer Res Date: 2000-09 Impact factor: 12.531
Authors: Owen A O'Connor; Barbara Pro; Lauren Pinter-Brown; Nancy Bartlett; Leslie Popplewell; Bertrand Coiffier; Mary Jo Lechowicz; Kerry J Savage; Andrei R Shustov; Christian Gisselbrecht; Eric Jacobsen; Pier Luigi Zinzani; Richard Furman; Andre Goy; Corinne Haioun; Michael Crump; Jasmine M Zain; Eric Hsi; Adam Boyd; Steven Horwitz Journal: J Clin Oncol Date: 2011-01-18 Impact factor: 44.544