A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors Journal Article
| Authors: | Fury, M. G.; Krug, L. M.; Azzoli, C. G.; Sharma, S.; Kemeny, N.; Wu, N.; Kris, M. G.; Rizvi, N. A. |
| Article Title: | A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors |
| Abstract: | Purpose: The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans. Methods: The starting dose was pralatrexate 40 mg/m 2 intravenously and probenecid 70 mg/m 2 intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1. Results: Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m 2 and probenecid 233 mg/m . Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen. Conclusion: For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m 2 and probenecid 140 mg/m 2. Vitamin B 12 and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study. © Springer-Verlag 2005. |
| Keywords: | adult; clinical article; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; unclassified drug; clinical trial; constipation; fatigue; neutropenia; advanced cancer; area under the curve; cancer combination chemotherapy; diarrhea; solid tumor; cancer patient; neoplasms; edema; controlled clinical trial; drug eruption; sensory neuropathy; anemia; blood toxicity; gastrointestinal symptom; leukopenia; neuropathy; stomatitis; thrombocytopenia; antineoplastic combined chemotherapy protocols; myalgia; dose-response relationship, drug; alanine aminotransferase blood level; arthralgia; aspartate aminotransferase blood level; coughing; febrile neutropenia; alanine aminotransferase; aspartate aminotransferase; bilirubin; chemotherapy induced emesis; peripheral edema; nausea and vomiting; vitamin supplementation; area under curve; hyperbilirubinemia; folic acid; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; abnormally high substrate concentration in blood; folic acid antagonist; drug dose regimen; alopecia; pralatrexate; aminopterin; solid tumors; bone marrow disease; blurred vision; cyanocobalamin; phase i; probenecid; liver pain; aminopterin derivative |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 57 |
| Issue: | 5 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2006-05-01 |
| Start Page: | 671 |
| End Page: | 677 |
| Language: | English |
| DOI: | 10.1007/s00280-005-0080-x |
| PUBMED: | 16136310 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 9" - "Export Date: 4 June 2012" - "CODEN: CCPHD" - "Source: Scopus" |
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