Abstract
14608 Background: Preclinical studies of calcitriol and vitamin D analogs demonstrate potent growth inhibition of tumor cell lines. The clinical development of calcitriol and other analogs have been hindered by hypercalcemia. 1α (OH)D2 is a Vitamin D analog which has produced objective responses in advanced androgen-independent prostate cancer patients and can be administered daily at 10mcg. LR103 is an active metabolite of 1α (OH)D2 with equivalent anti-tumor activity and significantly less calcemic effects in preclinical studies. This phase I study explores the maximal tolerated dose and toxicity of LR-103. Methods: LR-103 was administered daily beginning at a dose of 5 μg/day with a cycle length of 14 to 28 days. Dose escalation proceeded in two stages. In step A, intra-patient dose escalation (starting dose of 5mcg daily) was allowed based on degree of toxicity regardless of attribution. Step A escalation continued until 2 patients had ≥ grade 2 toxicity at a dose level. Step B is a standard, inter-patient only, dose-escalation trial (starting dose based on Step A) with cohorts of three. Dose limiting toxicity is defined as ≥ grade 3 toxicity. Results: Nineteen patients have enrolled between May and December 2005, eight to step A and eleven to step B. During step A escalation, two patients at 15 μg/day experienced severe toxicity (grade 4 hyperuricemia and grade 3 alkaline phosphatase) and two patients at 15 μg/day experienced grade 1 hypercalcemia. Hypercalciuria has been common. No hypercalcemia ≥ grade 2 has been observed. Step B enrollment continues at 30 μg/day without hypercalcemia. Conclusions: Daily administration of LR-103 has not resulted in significant hypercalcemia to date. Dose escalation continues. No significant financial relationships to disclose.
Published Version
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