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

Kevin R. Kelly, Nashat Gabrail, Steven Weitman, John Sarantopoulos, Anthony J. Olszanski, William Edenfield, Jurgen Venitz, Guru Reddy, Allen Yang, Steven J. Hasal, Albert Lockhart

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)929-939
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume78
Issue number5
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

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Pharmacokinetics
Refractory materials
Tumors
Lymphoma
Kidney
Safety
Neoplasms
Toxicity
10-propargyl-10-deazaaminopterin
T-cells
Folic Acid
Peripheral T-Cell Lymphoma
Labels
Plasmas

Keywords

  • Lymphoma
  • Pharmacokinetics
  • Pralatrexate
  • Renal

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

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. / Kelly, Kevin R.; Gabrail, Nashat; Weitman, Steven; Sarantopoulos, John; Olszanski, Anthony J.; Edenfield, William; Venitz, Jurgen; Reddy, Guru; Yang, Allen; Hasal, Steven J.; Lockhart, Albert.

In: Cancer Chemotherapy and Pharmacology, Vol. 78, No. 5, 01.11.2016, p. 929-939.

Research output: Contribution to journalArticle

Kelly, Kevin R. ; Gabrail, Nashat ; Weitman, Steven ; Sarantopoulos, John ; Olszanski, Anthony J. ; Edenfield, William ; Venitz, Jurgen ; Reddy, Guru ; Yang, Allen ; Hasal, Steven J. ; Lockhart, Albert. / 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. In: Cancer Chemotherapy and Pharmacology. 2016 ; Vol. 78, No. 5. pp. 929-939.
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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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T1 - 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

AU - Kelly, Kevin R.

AU - Gabrail, Nashat

AU - Weitman, Steven

AU - Sarantopoulos, John

AU - Olszanski, Anthony J.

AU - Edenfield, William

AU - Venitz, Jurgen

AU - Reddy, Guru

AU - Yang, Allen

AU - Hasal, Steven J.

AU - Lockhart, Albert

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

KW - Lymphoma

KW - Pharmacokinetics

KW - Pralatrexate

KW - Renal

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