Phase (Ph) I evaluation of the dolastatin analogue synthadotin (SYN-D; ILX651): Pooled data analysis of three alternate schedules in patients (pts) with advanced solid tumors

Abstract

3068 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 has been chemically modified to improve pharmacological properties and is orally bioavailable with a therapeutic window potentially enhanced over previous generations of dolastatins. Methods: Three Ph I studies were conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of SYN-D when given for 30-mins IV q3wk on d 1–5 (A1, 36 pts) and d 1, 3, 5 (A2, 32 pts) or q4wk on d 1, 8, 15 (A3, 30 pts). Cohorts of 1–6 pts were treated at the following dose ranges (mg/m2): A1 2.3–36.3; A2 3.9–45.7; A3 7.8–62.2. Pooled baseline pt characteristics (n=93): M/F=47/46; ECOG 0/1/2= 23/57/13; median age=59; mean # cycles=2.8 (1–17). Results: The MTD (mg/m2/d)/dose intensity (DI) (mg/m2/wk) were: A1 27.3/45.5; A2 34.4/34.4; and A3 46.8/35.1. The DLT (all 3 schedules) was neutropenia (Nu). Overall, Nu was predictable (d 15), self-limited and occurred in 36% of pts. Other noted toxicities: fatigue 46%; N/V 40%/30%; anorexia 25%; and diarrhea 24%. Peripheral neuropathy, non-cumulative, was noted in only 6% of pts (G1–2). Risk factor analysis revealed that duration on study (mean # days) was longer for pts who had Nu (G1–4, 76–96) versus those who did not (53) and that neither prior platinum nor age (≤60/>60) predisposed pts to Nu. One pt (A1) with melanoma with liver/bone metastases experienced a CR for >1 year. One pt (A3) with NSCLC, previously treated with paclitaxel and docetaxel, had 47% tumor decrease for 5 months. Another 24 pts had SD distributed as follows: A1 31%, A2 31%, A3 16% (4/25). The mean days on study for responders (CR/MR/SD) and non-responders (PD) was 133 and 40, respectively. Conclusions: Schedule A1, which maximizes DI without compromising safety, is under evaluation in the Ph II setting in melanoma and NCSLC and is planned in prostate and in an opportunistic tumor study design. 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 Products, Inc. ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Products, Inc., an affiliate of ILEX Oncology