title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA kbwisinski@medicine.wisc.edu.
authors.forename: Kari B
authors.initials: KB
authors.lastname: Wisinski
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Ledesma
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Statistics, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Douglas
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Traynor
authors.forename: Mark
authors.initials: M
authors.lastname: Albertini
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mulkerin
authors.affiliation: UW School of Medicine and Public Health, University of Wisconsin (UW) Carbone Cancer Center, Madison, WI, USA.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004872:Ergocalciferols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced; D053565:Hypercalciuria / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018763:Muscle Fatigue; D009369:Neoplasms / Q000188:drug therapy*; D015675:Osteocalcin / Q000097:blood; D010281:Parathyroid Hormone / Q000097:blood; D014552:Urinary Tract Infections / Q000150:complications
chemical_list: D000970:Antineoplastic Agents; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D015675:Osteocalcin; C063087:1,24-dihydroxyvitamin D2; D000469:Alkaline Phosphatase; D002118:Calcium
keywords: Vitamin D; cancer; phase I