Phase I, pharmacokinetic (PK) study of synthadotin (SYN-D; ILX651), a next generation antitubulin, administered iv weekly x 3 weeks every 4 weeks (wx3q4w)

Abstract

3073 Background: SYN-D is a pentapeptide with a unique mechanism of action that potentially differs from microtubule stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and other dolastatins) as it is postulated to inhibit microtubule nucleation. SYN-D possesses broad, potent antitumor activity, and favorable pharmacological and toxicity profiles preclinically, particularly with respect to cardiovascular effects. Methods: Based on the protracted nature of binding and retention of tubulin-binding agents in peripheral tissues and tumors, SYN-D administered IV for 30 mins wx3q4w was evaluated. The maximum tolerated dose (MTD) was the highest dose at which <2/6 new pts experienced dose-limiting toxicity (DLT) in course 1. Results: Thirty pts stratified by prior myelotoxic therapy into minimally and heavily pretreated (MP and HP, respectively) cohorts (median age 56; M/F=18/12; tumor types: colorectal [13], renal [4], melanoma [4] breast [2], NSCLC [2], larynx, ovary, mesothelioma, HCC and prostate cancers [1 each]) were treated with 66 courses (range 1–6) of SYN-D at 7.8, 15.6, 31.2, 46.8, 54.5, and 62.2 mg/m2. Unacceptably high levels of dose-limiting neutropenia (precluding day 15 SYN-D administration; 1 complicated by fever) were seen in 2/3 MP pts treated at 62.2 mg/m2 and in 3 and 2 MP and HP pts, respectively, at 54.5 mg/m2. The MTD and recommended phase II dose for both cohorts is 46.8 mg/m2. At this dose level only 1/9 pts experienced DLT. No major gastrointestinal, neurological or cardiovascular toxicities were noted. Antitumor activity included a 47% decrease in a taxane- and platinum-refractory NSCLC lasting 5 months and stable disease >4 months in 2 pts with HCC and renal cancer. The PK behavior of SYN-D (dose range of 7.8–62.2 mg/m2) was biphasic; a third non-quantifiable gamma phase was observed in a few pts; and the effective t1/2 was <1 hour. Conclusions: Weekly administration of SYN-D is safe, active, convenient and well tolerated; however, dose intensity is lower (35mg/m2/wk) than with the daily x 5 every 21 days schedule (45.5mg/m2/wk) currently in phase II evaluation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Oncology, Inc. ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Oncology, Inc. ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Products, Inc., an affiliate of ILEX Oncology