AEZS-112
(oncology)
Therapeutic area
Oncology
Target indication
Solid tumors
Development stage
Phase 1
Description
The primary endpoints of the Phase 1 trial will focus on determining the safety and tolerability of AEZS-112 as well as establishing the recommended Phase 2 dose and regimen. Secondary endpoints are aimed at establishing the pharmacokinetics and determining the efficacy, based on standard responce criteria.
AEZS-112 is the first anticancer drug in development involving two mechanisms of action, tubulin and topoisomerase II inhibition. AEZS-112 expresses different modes of action such as, pro-apoptotic and anti-angiogenic properties.
Mode of action
Mode of action studies revealed that the compound AEZS-112 inhibits the polymerization of ß-tubulin in low micromolar concentrations. Competition studies suggest that AEZS-112 interacts with the same binding site on microtubules as colchicine. AEZS-112 destroys the mitotic spindles of the cancer cells, arrests the cancer cells in G2/M phase at low concentrations, mediates DNA fragmentation via inhibition of topoisomerase II and induces apoptosis via various mechanisms.
Trial results
AEZS-112 has shown potent in vitro anti-proliferative activity at nanomolar concentrations against human tumor cell lines of different origin. AEZS-112 is active in tumor cell lines which are resistant to other tubulin inhibitors, cisplatin, vincristine and doxorubicin. Furthermore, it was shown that AEZS-112 inhibits the enzyme topoisomerase II at micromolar concentrations.
AEZS-112 given orally once or twice weekly proved to be a potent inhibitor of in vivo tumor growth in different models including mammary, colon, skin, lung, renal and leukemic cancers.
Early, orienting safety pharmacology and toxicology assessment revealed:
- Very good selectivity of AEZS-112 against a variety of receptors and enzymes (low side effect potential)
- No concerns regarding hERG inhibition in vitro by AEZS-112
- No behavioural changes observed in Irwin test with mice
- No mutagenic potential observed in AMES tests
Development plan
A Phase 1 trial with AEZS-112 including up to 50 patients with advanced solid tumors and lymphoma was completed in September 2009. Management is currently evaluating future development plans for AEZS-112.
The study was performed in two parts and included 42 patients overall. In Part I, 22 patients were studied on doses ranging from 13 to 800 mg/week. In Part II, the weekly dose was split into 3 doses taken 8 hours apart, and ultimately, 20 patients received doses from 120 to 600 mg/week. Stable disease with time to failure ranging from 20 to 60+ weeks was achieved in 12 patients with various cancer types, including melanoma and cancers of the colon/rectum, lung, pancreas, prostate, tongue, trachea and thyroid. In several of these patients, the duration of stabilization exceeded the duration of disease control on previous treatment regimens. Except for a dose-limiting gastrointestinal reaction in a patient with pre-existing GI problems, no clinically relevant drug-related adverse events or changes in laboratory safety parameters were observed.
Partnership status
Æterna Zentaris owns the worldwide rights.
