Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies

Abstract

3076 Background: AP23573, a non-prodrug rapamycin analog, potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient signaling pathways. AP23573 demonstrated potent inhibition of proliferation in vitroin several human tumor cell lines and elicited antitumor activity in vivo in multiple xenograft animal models. Methods: This dose escalation trial utilizes an accelerated titration scheme to determine safety, tolerability and maximum tolerated dose of AP23573 administered without premedication as 30-minute IV infusion daily x 5 days every 2 weeks for 4-week cycles. It also is designed to characterize the PK profile, evaluate potential PD markers using western blot analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of skin biopsies, and ascertain preliminary data on antitumor activity. Results: As of 01 Dec 03: 11 pts (6M/5F), median age 57 yrs (range 23–65 yrs), were treated with AP23573 doses ranging from 3 to 28 mg in 5 dose level cohorts (total cycles, 32; median cycles, 2/pt). No dose-limiting toxicity or AP23573-related serious adverse events have been observed. Side effects for first cycle included grade (gr) 2 anemia (2 pts); gr 3 transient transaminase elevation (1 pt with hepatocellular cancer); gr 2 mucositis (2 pts); gr 1 skin rash (2 pts). PK analyses (doses 3 to 12.5 mg) suggest a mean AP23573 half-life of 44–54 hours. PD analyses (doses 3 and 6.25 mg) indicate rapid (within 1 hr) and prolonged (up to 10 days between doses) inhibition of mTOR activity as demonstrated by >80% decrease in phosphorylated 4EBP1 levels in PBMCs. Of 8 evaluable pts, one partial response has been observed in a pt with metastatic renal cell cancer; (6.25 mg) and 1 pt with metastatic sarcoma (3 mg) has had stable disease > 6 months. Conclusions:AP23573 can be administered safely using this schedule, and has exhibited antitumor activity as well as evidence of a substantial PD effect. Patient dosing and enrollment are ongoing. Further dose escalation as well as exploration of the relationship between PD (PBMC and skin) and PK are planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc.