Trial Information

Phase II Study of Weekly Carboplatin and Taxotere in Platinum Sensitive Relapsed Ovarian or Tubal or Primary Peritoneal Cancers

Ovarian cancer is the sixth most common malignancy in women, with estimated 2500 cases
diagnosed in 2001, and 1500 deaths. Despite maximal cytoreductive therapy, followed
normally by a taxane and carboplatin (or cisplatin) chemotherapy, most patients will
relapse, and require chemotherapy in a palliative setting. The goal of this second line
therapy is to prolong survival and to improve quality of life. This disease has been
characterized as chronic, as many patients may eventually go on to respond to additional
lines of therapy.

Response to second line therapy has been correlated to length of time since the end of the
first line treatment (treatment free interval, TFI). Patients relapsing or progressing
while on therapy are defined as platinum-refractory. In North America the norm is to label
patients with a TFI of 6 months or less as platinum-resistant. A TFI of greater than 6
months would make a patient platinum-sensitive.

These platinum-sensitive patients are generally treated with single agent carboplatin or
carboplatin and taxol by 3-weekly administration. The ICON-4 trial published in June 2003
compared single agent platinum to combination of platinum-taxol. Patients could have
received one or both of these agents in the adjuvant setting. At a median follow-up of 42
months the absolute difference in 2-year survival was 7% [P=0.0004} in favor of the
combination arm. Thus combination platinum-taxol is the present standard of care in
platinum-sensitive relapsed ovarian cancer. Use of taxol is limited by persistent neuropathy
in 20%.

Presently there is growing evidence in support of giving chemotherapy at shorter intervals
at low-doses. Hypothetically, this allows less advancement of cancer cells through the cell
cycle. Moreover weekly taxanes are associated with an anti-angiogenic effect- more so with
taxotere than taxol in cell-lines.

Several randomized trials in breast cancer have shown the improved efficacy of weekly taxol
over 3-weekly taxol. The neoadjuvant study showed an increase in pCR [complete response on
pathologic evaluation] of 10%with weekly taxol. The adjuvant study with 2-weekly
chemotherapy showed a 7% improvement in time-to-progression over 3-weekly chemotherapy.

In ovarian cancer- a Phase II study of weekly carboplatin (AUC-2) with taxol (80mg/m2/week)
given on day 1,8,15 of 28 day cycles has shown a response rate of 100% [80% CR, 20% PR] in
21 platinum-sensitive patients- with either measurable or evaluable disease. Median duration
of response was 11.7 months (95% CI- 8.0-18.5 months). 46% reported Grade I neuropathy, 1
patient had febrile neutropenia, and 32% had Grade 3 neutropenia.

Weekly administration of taxotere with carboplatin has been studied in a Phase I study.
Maximum tolerated dose was Taxotere 35mg/m2 with carboplatin AUC-2. At this dose no Grade 3
or 4 cytopenias were seen. Nor were there significant neuropathies.

Our study plans to evaluate Taxotere 35mg/m2 with Carboplatin at AUC-2 given weekly. 3
weekly treatments will constitute one cycle. We expect to see equivalent response rates and
equivalent or higher duration of responses with better toxicity profile.