Phase I trial of 1alpha-hydroxyvitamin d(2) in patients with hormone refractory prostate cancer.
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.
Liu
Glenn
G
University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, USA.
Oettel
Kurt
K
Ripple
Gregory
G
Staab
Mary Jane
MJ
Horvath
Dorothea
D
Alberti
Dona
D
Arzoomanian
Rhoda
R
Marnocha
Rebecca
R
Bruskewitz
Reginald
R
Mazess
Richard
R
Bishop
Charles
C
Bhattacharya
Abhik
A
Bailey
Howard
H
Wilding
George
G
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
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