Trial Information

A Phase II Non-randomized Study of DOXIL Consolidation Treatment for Ovarian Cancer, Cancer of the Fallopian Tube or Peritoneal Carcinoma.

While the majority of subjects with advanced ovarian cancer will respond well to the initial
chemotherapy regimen of taxol/platinum, these responses are generally of limited duration.
Even women who have a surgically defined complete response to initial chemotherapy have >50%
recurrence rate in Stage III disease. Once ovarian cancer has recurred it is rare that cure
is possible, therefore, there is a critical need to define new therapeutic strategies in the
treatment of ovarian cancer. Consolidation chemotherapy is one possible strategy. The
strategy behind consolidation chemotherapy institutes second-line chemotherapy immediately
following a clinical response but before evidence of recurrence. This strategy has gained
popularity with many oncologists, secondary to the results of GOG 178, a large study by the
Southwest Oncology Group and the Gynecologic Oncology Group. GOG 178 set out to explore
both efficacy and patient tolerability in the consolidation setting. Moreover, the
objective of the GOG 178 study was to compare two different durations of consolidation
treatment using taxol consolidation in clinically NED ovarian cancer subjects following
primary chemotherapy of carbo/taxol. The results of GOG178 suggested that a longer course
(12 vs. 3 cycles of paclitaxel) gave subjects a longer median progression-free survival (28
vs. 21 months). This trial was closed early due to a statistically improved PFS in subjects
receiving 12-month regimen of paclitaxel versus the 3 month regimen. Unfortunately, we will
never definitively learn if this improved PFS translates to improved survival for ovarian
cancer patients. A limitation of this regimen is the cumulative and sometimes irreversible
side effect of neuropathy. Doxil has been selected in this consolidation trial due to
documented success in second- line setting with ovarian cancer subjects without long term
negative sequelae such as neuropathy The anthracycline antibiotic doxorubicin has a broad
spectrum of antineoplastic action and a correspondingly widespread degree of clinical use.
In addition to its role in the treatment of ovarian cancer, doxorubicin is indicated in the
treatment of Hodgkin's disease and non-Hodgkin's lymphoma, hepatocellular and gastric
carcinoma, small cell cancer of the lung, soft tissue and bone sarcomas, as well as cancer
of the breast, bladder, and thyroid. Unfortunately, toxicity limits the therapeutic
activity of doxorubicin and may preclude adequate dosing.

The conventional formulation of the drug is rapidly cleared from the bloodstream and has a
very large volume of distribution, which may contribute to the drug's toxicity. High
cumulative doses of doxorubicin generally must be avoided because of the potential for
cardiotoxicity, while individual doses are often limited by myelosuppression. Alopecia
typically develops and persists throughout treatment. Severe acute nausea and vomiting,
stomatitis, and esophagitis are additional adverse effects of doxorubicin that may
necessitate dose-reduction or discontinuation of the drug. A doxorubicin formulation with
improved tolerability might increase the drug's therapeutic ratio and thus enhance its
efficacy.

Liposomal encapsulation of doxorubicin may reduce both the nonspecific drug delivery to
normal tissues as well as the high peak plasma levels of free drug responsible for its
toxicity. At the same time, a liposomal formulation may deliver doxorubicin to tumors with
improved specificity. Doxil is a doxorubicin formulation in which the drug is encapsulated
in liposomes (Stealthâ liposomes) that escape instant recognition and uptake by the
mononuclear phagocyte system. As a result, the formulation has a long circulation time, and
the liposomes can eventually become extravasated through the abnormally permeable vessels
characteristic of many tumors. Once concentrated in tumors the liposomes of Doxil can
deliver high levels of doxorubicin to malignant cells, without affecting normal tissue.1

Doxil is approved by the FDA for use in subjects with ovarian cancer whose disease has
progressed or recurred after platinum-based chemotherapy and in subjects with HIV Kaposi's
Sarcoma. Doxil established efficacy as a single agent in recurrent ovarian cancer as a
result of three open-label, single-arm clinical studies of 176 subjects with metastatic
ovarian cancer. Subjects in these studies received Doxil at 50mg/m2 infused over one hour
every 3 or 4 weeks for 3-6 cycles or longer in the absence of dose-limiting toxicity or
progression of disease. Doxil has been used for several years as a 2nd line chemotherapy
agent. In the randomized Phase III study of subjects with recurrent ovarian cancer by
Gordon et al, there was an 18% reduction in the risk of death for subjects treated with
Doxil (median survival 62.7weeks) compared to topotecan (median survival 59.7 weeks). In
platinum sensitive subjects (who recurred after more than six months), the reduction in risk
of death was even more dramatic, a 30% reduction was noted in the subjects who received
Doxil (median survival 107.9 weeks) versus topotecan (median survival 70.1 weeks). In this
trial Doxil 50mg/m2 was administered every 28 days, resulting in 23.4% of the subjects with
grade 3 or 4 hand foot syndrome (HFS). 4 Management of this side effect included
increasing the dosage interval and/or decreasing the dose by 25%. Today, Doxil 40mg/m2
every 28 days is commonly used for treatment of recurrent ovarian cancer. Rose et al
reported their results from a retrospective review noting the 40mg/m2 dose every 28 days
minimizes toxicity without sacrificing efficacy.6

Experience has taught us this toxicity can be minimized with patient education focusing on
alteration of activities in the day preceding and 3-5 days follow drug administration. Other
side effects such as bone marrow suppression, alopecia, nausea, vomiting, and fatigue are
minimal. There have been several small trials using weekly and bi-weekly Doxil® in cancer
patients, including breast, gastric, pancreatic and colon cancer, in an attempt to reduce
the incidence of hand foot syndrome with encouraging results

This study will evaluate the efficacy of Doxil in clinically NED ovarian cancer subjects
following standard platinum/taxane based therapy. Applying every two-week dosing of Doxil
20mg/m2 as this is expected to minimize the most problematic side effect, HFS.