AEZS-108 (doxorubicin peptide conjugate) is a targeted cytotoxic peptide conjugate which is a hybrid molecule composed of a synthetic peptide carrier and a well-known cytotoxic agent, doxorubicin. The design of this product allows for the specific binding and selective uptake of the cytotoxic conjugate by the LHRH receptor-positive tumors. The binding of conjugate molecule AEZS-108 to cancerous cells that express these receptors results in its accumulation in the malignant tissue. This binding is followed by internalization and retention of the cytotoxic drug, doxorubicin, in the cells. Therefore, since they target specific cells, cytotoxic conjugates are postulated to be more effective and have less side-effects than the respective non-conjugated/non-linked cytotoxic agents in inhibiting tumor growth.
AEZS-108 is the first drug in a clinical study that targets the cytotoxic activity of doxorubicin specifically to LHRH-receptor expressing tumors.
Results - Phase 2 study in ovarian cancer:
On June 6, 2010, positive efficacy and safety data for our doxorubicin targeted conjugate compound, AEZS-108, in ovarian cancer were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. 42 patients with platinum-resistant ovarian cancer entered the study. Patients received a recommended dose of 267 mg/m2 by intravenous infusion over 2 hours, with retreatment every 3 weeks, for up to 6 courses. Response rate (RECIST and/or GCIG criteria) was defined as primary endpoint. Secondary endpoints were safety, time-to-progression (TTP) and overall survival (OS).
Results:
Efficacy included partial response in 5 patients (11.9%) and stable disease for more than 12 weeks in 11 patients (26.2%). Based on those data, a Clinical Benefit Rate (CBR) of 38% can be estimated. Median time to progression (TTP) and overall survival (OS) were 3.5 months (104 days) and 15.6 months (475 days), respectively.
Conclusions:
- AEZS-108 was active and well tolerated in patients with heavily pre-treated platinum and taxane resistant ovarian cancer;
- The safety profile confirmed the dose of 267 mg/m2;
- Hematological toxicity was rapidly reversible;
- Non-hematological toxicities were usually limited to lower severity;
- Tolerability and CBR compare favourably with topotecan and liposomal doxorubicin;
- Overall survival is encouraging as all patients treated with AEZS-108 were platinum-resistant.
Results - Phase 1 portion of ongoing Phase 1/2 study in prostate cancer:
On February 3rd 2012, positive updated results for the Phase 1 portion of our ongoing Phase 1/2 study in castration- and taxane-resistant prostate cancer (CRPC) were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium. Data showed that AEZS-108 was well tolerated and demonstrated early evidence of antitumor activity in men with CRPC.
Patients received AEZS 108 intravenously over 2 hours every 3 weeks for up to 6 cycles, until progression of the disease, unacceptable toxicity or patient withdrawal. Premedication included dexamethasone 8 mg.
Currently, 13 patients have been treated on 3 dose levels: 3 at 160 mg/m2, 3 at 210 mg/m2, and 7 at 267 mg/m2. Overall, AEZS-108 has been well tolerated among this group of heavily pre treated older patients. To date, there have been 2 dose limiting toxicities; both were cases of asymptomatic grade 4 neutropenia at the 267 mg/m2 dose level and both patients fully recovered. The grade 3 and 4 toxicities were primarily hematologic. There has been minimal non-hematologic toxicity, most frequently fatigue and alopecia.
Despite the low doses of AEZS-108 in the first cohorts, there is some evidence of antitumor activity. One patient received 8 cycles (at 210 mg/m2) due to continued benefit. Among the 5 evaluable patients with measurable disease, 4 achieved stable disease. At the time of submission, a decrease in PSA was noted in 6 patients. Six of 13 (46%) treated patients have received at least 5 cycles of therapy with no evidence of disease progression at 12 weeks.
The trial is being supported by a three-year US$1.6 million grant from the National Institutes of Health to Dr. Pinski.
Results - Phase 1 study in gynecological cancers:
On June 3, 2007 positive results of an open, multi-center, sequential group, dose-escalation Phase 1 study in various gynecological cancers were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 17 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.
The study showed that AEZS-108 was well tolerated by patients with gynecological tumors. Signs of anti-tumor activity were observed in seven out of 13 patients treated with 160 or 267 mg/m2 of AEZS-108, including three patients with complete or partial response.
AEZS-108 has been granted orphan-drug designation by the FDA for ovarian cancer.
AEZS-108 is being investigated in Phase 2 trials in prostate, bladder and breast cancer.
Furthermore, a first pivotal trial in endometrial cancer was initiated during 1Q-2013, but recruitment has not yet started.
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