Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D3 analogue, in a phase I study of patients with advanced malignancies.
OBJECTIVE
Differentiation therapy is an alternative to chemotherapy with potentially less toxicity, improved quality of life, and survival. We conducted a phase I trial of ILX23-7553, a formulation of 1,25-dihydroxy-16-ene-23-yne-vitamin D(3), a 1,25-dihydroxyvitamin D(3) analog with preclinically demonstrated antitumor and differentiating effects and diminished hypercalcemic effects.


METHODS
The protocol consisted of five daily oral treatments during 14-day cycles at 15 dose levels from 1.3 to 45.0 mug/m(2)/day. We treated 42 heavily pretreated patients who had a variety of malignancies with 162 treatment cycles, and obtained pharmacokinetics from three patients at the two highest dose levels.


RESULTS
There were no grade 3 or 4 toxicities. Grade 1-2 toxicities included diarrhea, nausea, fatigue, constipation, and one grade 1 hypercalcemia. Average day 6 calcium was 9.26 +/- 0.55 mg/dl in cycle 1 and 9.30 +/- 0.67 mg/dl in cycle 2. Pharmacokinetics at dose levels 14 (40 mug/m(2)/day) (1 patient) and 15 (45 mug/m(2)/day) (2 patients) demonstrated an average C(max) of 30.4 +/- 7.8 pg/ml (0.07 nM) and 104 +/- 38.2 pg/ml (0.25 nM), and AUCs of 222.5 +/- 225.2 pg.h/ml and 855 +/- 536 pg h/ml, respectively. Eight patients (19%) had stable disease. While in vitro effects have been reported at these concentrations, they were at least 10-fold lower than ED(50)s, and the study was terminated before an MTD was reached.


CONCLUSIONS
The drug is safe and has potential benefits at serum concentrations where effects begin to be noted in vitro. Further study is needed with a reformulated higher unit dose compound to determine the safety and efficacy of higher serum concentrations.
Wieder
Robert
R
Division of Oncology/Hematology, Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA. wiederro@umdnj.edu
Novick
Steven C
SC
Hollis
Bruce W
BW
Bryan
Margarette
M
Chanel
Suzanne M
SM
Owusu
Kate
K
Camastra
Danielle
D
Saunders
Tracie
T
Pliner
Lillian
L
Harrison
Jonathan
J
Bonate
Peter
P
Williams
Tom
T
Soignet
Steven
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002762:Cholecalciferol / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005260:Female; D005767:Gastrointestinal Diseases / Q000097:blood / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy
C428283:ILX237553; D002762:Cholecalciferol