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

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Abstract

Purpose: 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 D3, a 1,25-dihydroxyvitamin D3 analog with preclinically demonstrated antitumor and differentiating effects and diminished hypercalcemic effects. Patients and methods: The protocol consisted of five daily oral treatments during 14-day cycles at 15 dose levels from 1.3 to 45.0 μg/m2/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 μg/m2/day) (1 patient) and 15 (45 μg/m2/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 ED50s, and the study was terminated before an MTD was reached. Conclusion: 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.

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Authors and Affiliations

  1. Division of Oncology/Hematology, Department of Medicine, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark, NJ

    Robert Wieder, Margarette Bryan, Kate Owusu, Tracie Saunders, Lillian Pliner & Jonathan Harrison

  2. Memorial Sloan-Kettering Cancer Center, Division of Solid Tumor Oncology, Department of Medicine, New York, NY

    Steven C. Novick, Suzanne M. Chanel, Danielle Camastra & Steven Soignet

  3. Department of Pediatrics, Medical University of South Carolina, Charleston, SC

    Bruce W. Hollis

  4. ILEX Products, Inc, San Antonio, TX

    Peter Bonate & Tom Williams

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  1. Robert Wieder
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  2. Steven C. Novick
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  3. Bruce W. Hollis
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  4. Margarette Bryan
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Wieder, R., Novick, S.C., Hollis, B.W. et al. Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D3 analogue, in a phase I study of patients with advanced malignancies. Invest New Drugs 21, 445–452 (2003). https://doi.org/10.1023/A:1026203418976

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