title: Phase I trial of 1alpha-hydroxyvitamin d(2) in patients with hormone refractory prostate cancer.
abstract: This Phase I study of 1alpha-hydroxyvitamin D(2), an p.o. administered vitamin D analogue, in patients with advanced hormone-refractory prostate cancer was designed to assess the toxicity, pharmacokinetic and biological markers of drug activity, and lastly tumor response data to recommend a dose for Phase II studies. 1alpha-Hydroxyvitamin D(2) was administered daily at doses ranging from 5 to 15 microg/day. Patients were monitored for toxicity and tumor response, and blood and urine samples were collected for pharmacokinetics (1alpha,25-dihydroxyvitamin D(2) levels) and other parameters of biological activity (bone markers, parathyroid hormone, urine calcium, and serum phosphorus levels). Twenty-five patients were enrolled. Main toxicities were hypercalcemia with associated renal insufficiency. No other significant toxicity was seen. Pharmacokinetics showed an increase in the active metabolite 1alpha,25-dihydroxyvitamin D(2) that reached a plateau by week 4 despite continuous drug dosing. Elevation in daily urinary calcium excretion and serum phosphorus levels was seen, whereas a decrease in serum parathyroid hormone was evident. Two patients showed evidence of a partial response, whereas 5 others achieved disease stabilization for > or =6 months. 1alpha-Hydroxyvitamin D(2) was well tolerated with main toxicities being hypercalcemia and renal insufficiency. All of the toxicity was reversible with drug discontinuation. Evidence for drug activity was seen in surrogate markers, and pharmacokinetic analysis showed substantial increases in vitamin D metabolite levels among the various cohorts. Whereas the defined maximum tolerated dose was not reached, the recommended Phase II dose was 12.5 microg/day given continuously.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.forename: Kurt
authors.initials: K
authors.lastname: Oettel
authors.forename: Gregory
authors.initials: G
authors.lastname: Ripple
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Staab
authors.forename: Dorothea
authors.initials: D
authors.lastname: Horvath
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Rhoda
authors.initials: R
authors.lastname: Arzoomanian
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Reginald
authors.initials: R
authors.lastname: Bruskewitz
authors.forename: Richard
authors.initials: R
authors.lastname: Mazess
authors.forename: Charles
authors.initials: C
authors.lastname: Bishop
authors.forename: Abhik
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Howard
authors.initials: H
authors.lastname: Bailey
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000097:blood; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D014408:Biomarkers, Tumor / Q000097:blood; D002118:Calcium / Q000652:urine; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D004872:Ergocalciferols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced; D007676:Kidney Failure, Chronic / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D015675:Osteocalcin / Q000097:blood; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D016879:Salvage Therapy; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004872:Ergocalciferols; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D011355:Prodrugs; D015675:Osteocalcin; D010758:Phosphorus; C042533:1 alpha-hydroxyergocalciferol; D017430:Prostate-Specific Antigen; D002118:Calcium