Efficacy and Safety and Pharmacokinetic Study of Avastin and Doxil in Ovarian Cancer

Treatment upon diagnosis of epithelial ovarian cancer (EOC) consists of surgery to achieve
maximal tumor debulking followed by platinum-based chemotherapy (carboplatin + paclitaxel).
Recently, optimally (e.g., < 1 cm residual disease) debulked patients appear to benefit from
regimens that include intraperitoneal administration of cisplatin. While complete response
(CR) is frequently achieved, by two years 50% of the patients show signs of recurrence.

When EOC presenting at an advanced stage recurs, even after a CR had been achieved, it can
no longer be totally eradicated. Nevertheless, a number of drugs lead to objective
responses, patients benefit with a prolongation of survival. Anti-tumor activity of Doxil
against ovarian cancer was noted in a phase I study, and this was followed by a phase II
study that demonstrated activity in platinum and paclitaxel refractory disease. In the
expanded phase II experience at the University of Southern California, responses to Doxil
occurred preferably in disease that was not bulky and after fewer prior treatments.
Typically, several cycles were required for maximum response, and some patients had
prolonged stable disease. Subsequently, the study of Gordon et al established the preferred
role of this drug formulation in the 2nd line-setting. It is logical, therefore, to build
on this agent in trying to improve the outcome of patients with recurrent ovarian cancer,
and in particular, to consider a combination with Avastin, since Avastin has shown agent
activity in retrospective data and recent studies in EOC.

A combination of Doxil with Avastin has several aspects of interest to ovarian cancer
treatment: 1) independent single-agent activity, 2) enhanced localization of Doxil is
possible via increased half-life (if liposomal egress is diminished) and decreased tumoral
interstitial pressure, 3) improved Doxil distribution, and 4) likely favorable toxicity
profile since Doxil's only common problematic toxicity is to the skin (palmar-plantar
erythrodysesthesia or PPE). Pharmacokinetic issues will be addressed in selected patients,
by comparing cycle 1 (without Avastin) with cycle 2 (with Avastin).