Journal Article

Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D3 analogue, in a phase I study of patients with advanced malignancies

Pliner, Lillian, Bonate, Peter, Chanel, Suzanne M., Harrison, Jonathan, Soignet, Steven, Novick, Steven C., Hollis, Bruce W., Williams, Tom, Owusu, Kate, Saunders, Tracie, Bryan, Margarette, Wieder, Robert, Camastra, Danielle

2003

Overview

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. 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. 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. 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.

• Publisher: Kluwer
• Subject: Adult / Aged / Aged, 80 and over / Antineoplastic agents / Area Under Curve / Biological and medical sciences / Chemotherapy / Cholecalciferol - administration & dosage / Cholecalciferol - adverse effects / Cholecalciferol - analogs & derivatives / Cholecalciferol - pharmacokinetics / Female / Gastrointestinal Diseases - blood / Gastrointestinal Diseases - chemically induced / Humans / Male / Medical sciences / Middle Aged / Neoplasms - blood / Neoplasms - drug therapy / Pharmacology. Drug treatments