A phase i study to determine the maximum tolerated dose and safety of oral LR-103 (1α,24(S)Dihydroxyvitamin D2) in patients with advanced cancer

Kari B. Wisinski, Wendy M. Ledesma, Jill Kolesar, George Wilding, Glenn Liu, Jeffrey Douglas, Anne M. Traynor, Mark Albertini, Daniel Mulkerin, Howard H. Bailey

Research output: Contribution to journalArticle

Abstract

Background The objective of this study was to determine the maximum tolerated dose and safety of LR-103, a Vitamin D analogue, in patients with advanced cancer. Methods In Step A, patients received oral LR-103 once daily in 14-day cycles with intra-patient dose escalation per accelerated dose escalation design. Dose limiting toxicity for Step A was defined as ≥ grade 2 hypercalcemia and/or >grade 2 other toxicities. Starting dose was 5 μg/day. Step B used a 3+3 design starting at Step A maximum tolerated dose with 28-day cycles. Dose limiting toxicity was defined as ≥ grade 3 hypercalcemia or any grade 3 or 4 non-hematologic toxicity, except hypercalciuria. Results Twenty-one patients were enrolled; eight were treated in Step A. At dose level 3 (15 μg/day), two patients had dose limiting toxicity. One had grade 4 hyperuricemia. The other had grade 4 GGT plus grade 3 alkaline phosphatase, fatigue and urinary tract infection (UTI). Dose level 2 (10 μg/day) was the maximum tolerated dose for Step A and was starting dose for Step B. The dose was escalated to dose level 5 (30 μg/day) with a patient experiencing grade 3 dose limiting toxicity of hypercalcemia. The study was discontinued before reaching the maximum tolerated dose due to sponsor decision. Modest increases in serum osteocalcin and calcium and decrease in parathyroid hormone were noted. Best response was stable disease; four patients were on therapy for six months or longer. Conclusion Step A dose limiting toxicities limited accelerated dose escalation. The maximum tolerated dose of LR-103 was not reached prior to study termination and this agent is no longer being developed.

Original languageEnglish (US)
Pages (from-to)416-424
Number of pages9
JournalJournal of Oncology Pharmacy Practice
Volume21
Issue number6
DOIs
StatePublished - Dec 1 2015

Keywords

  • Vitamin D
  • cancer
  • phase I

ASJC Scopus subject areas

  • Oncology
  • Pharmacology (medical)

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    Wisinski, K. B., Ledesma, W. M., Kolesar, J., Wilding, G., Liu, G., Douglas, J., Traynor, A. M., Albertini, M., Mulkerin, D., & Bailey, H. H. (2015). A phase i study to determine the maximum tolerated dose and safety of oral LR-103 (1α,24(S)Dihydroxyvitamin D2) in patients with advanced cancer. Journal of Oncology Pharmacy Practice, 21(6), 416-424. https://doi.org/10.1177/1078155214541572