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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

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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.

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Author information

Authors and Affiliations

  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 R. Kelly

  2. Gabrail Cancer Center Research, 4875 Higbee Ave. NW, Canton, OH, 44718, USA

    Nashat Gabrail

  3. UT Health Science Center, Cancer Therapy and Research Center, 7979 Wurzbach Road, San Antonio, TX, 78229, USA

    Steven Weitman & John Sarantopoulos

  4. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA

    Anthony J. Olszanski

  5. Greenville Hospital Systems Institute for Translational Oncology Research, 900 West Faris Rd CTC, 3rd Floor, CRU, Greenville, SC, 29605, USA

    William Edenfield

  6. Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 N 12th Street, P.O. Box 980533, Richmond, VA, 23298-0533, USA

    Jurgen Venitz

  7. Spectrum Pharmaceuticals, Inc., 157 Technology Dr., Irvine, CA, 92618, USA

    Guru Reddy, Allen Yang & Steven J. Hasal

  8. Washington University School of Medicine, 660 Euclid Avenue, St. Louis, MO, 63110, USA

    A. Craig Lockhart

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  1. Kevin R. Kelly
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  2. Nashat Gabrail
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  3. Steven Weitman
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  4. John Sarantopoulos
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  5. Anthony J. Olszanski
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  6. William Edenfield
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  7. Jurgen Venitz
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  8. Guru Reddy
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  9. Allen Yang
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  10. Steven J. Hasal
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  11. A. Craig Lockhart
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Corresponding author

Correspondence to Kevin R. Kelly.

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Conflict of interest

Guru Reddy, Allen Yang, and Steven Hasal are full-time employees of Spectrum Pharmaceuticals Inc. Kevin Kelly has served as a consultant for Spectrum Pharmaceuticals.

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Kelly, K., Gabrail, N., Weitman, S. et al. 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. Cancer Chemother Pharmacol 78, 929–939 (2016). https://doi.org/10.1007/s00280-016-3142-3

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  • DOI: https://doi.org/10.1007/s00280-016-3142-3

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