AEterna Zentaris presents detailed Phase I results for anti-cancer compound

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AEterna Zentaris Inc. presented a poster outlining detailed Phase I results for its targeted cytotoxic luteinizing hormone-releasing hormone (LHRH) analog, AEZS-108 (formerly named AN-152 and ZEN-008), in female patients with cancers expressing LHRH receptors. Evidence of anti-tumor activity was found at 160 mg/m2 or 267 mg/m2 doses of AEZS-108, where seven of 13 patients showed signs of tumour response, including three patients with complete or partial responses.

David J. Mazzo, Ph.D., president and CEO of AEterna Zentaris commented, "the outcome of this study with AEZS-108 is very encouraging as we are preparing to initiate our Phase II trial in endometrial and ovarian cancers. We believe that our targeted approach, including only patients with LHRH receptor expressing tumours, is the key to both individual patient safety and clinical benefit as well as the potential success of the upcoming trial."

This open, multi-center, sequential group, dose-escalation Phase I study assessed dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of AEZS-108 given once every three weeks in female patients with cancers expressing LHRH receptors. Safety monitoring included secretory function of the pituitary gland and cardiac function, while adverse events were calculated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE). Tumour response was evaluated according to Response Evaluation Criteria In Solid Tumours (RECIST) and by measuring tumour marker levels (CA125). High performance liquid chromatography (HPLC) with fluorescence detection was used for plasma PK of AEZS-108 and free doxorubicin.

Seventeen patients with LHRH receptor-positive ovarian, endometrial or breast cancers were recruited. AEZS-108 was administered by intravenous infusion over two hours at dosages of 10, 20, 40, 80,160 and 267 mg/m2. At 160 mg/m2, six patients had a total of 32 cycles and at 267 mg/m2, seven patients had a total of 27 cycles. Most of the patients had been pretreated with various chemotherapies.

Leucopenia/neutropenia of CTCAE Grade 4 was dose limiting in two of seven patients at 267 mg/m2. The patients recovered spontaneously from hematoxicity without use of hematopoietic growth factors. The most frequently observed non-hematological toxicities were alopecia, nausea and fatigue. Most toxicities were of Grade I. Two patients at the dose levels of 160 and 267 mg/m2 had a moderate allergic skin reaction (CTCAE Grade 2) during the first infusion; subsequent cycles with anti-allergic pre-medication were tolerated. No indication of cardiac toxicity or impairment of the pituitary gland function was reported.

Regarding tumour response, at 160 mg/m2, one patient with ovarian cancer showed the complete disappearance of a malignant lymph node (diameter 17 mm) at the first follow-up and received a total of six treatment cycles. Another patient showed stable disease for six cycles and one patient had stable disease until cycle 5.

At 267 mg/m2 one patient with ovarian cancer had a partial response of liver metastasis which was accompanied by a complete normalization of CA125 levels. Additionally, one patient showed complete CA125 tumor marker response (no evaluable target lesions in this patient) and received six treatment cycles. Finally, two patients showed stabilization of disease under treatment with 267 mg/m2 of AEZS-108 and were treated with five and six treatment cycles, respectively. In one of these patients, an additional transient minor tumor regression was observed.

PK analyses showed dose-dependent plasma levels of AEZS-108 and only minor (10-30%) release of doxorubicin.