Paclitaxel, Carboplatin and Vorinostat for the Treatment of Advanced Stage Ovarian Carcinoma

Ovarian cancer is the fifth most common cancer in women, accounting for nearly 15,280 deaths
annually in the United States [1]. Paclitaxel and Carboplatin are currently the accepted
standard of care for first line treatment of ovarian cancer [2, 3]. In spite of standard
chemotherapy, nearly 70% of patients succumb to this disease. Consequently, studies continue
to examine the activity of new agents and dosing regimens to improve disease free intervals
and overall survival.

There have been recent data suggesting that weekly chemotherapy regimens may significantly
benefit cancer patients' prognosis [4, 5]. Non-small cell lung cancer patient studies
employing weekly regimens have shown comparable response and survival rates to Q3 weekly
dosing schedules, with a more favorable toxicity profile [6, 7]. Further studies have
suggested that weekly Taxane dosing is at least as effective, less toxic, and more
convenient than traditional regimens [4, 8, 9].

The favorable activity associated with weekly chemotherapy has primarily been studied in
recurrent ovarian cancer patients, investigating the efficacy of single and/or combination
drug regimens [10, 11]. However, there have been some studies involving chemo-naïve patients
[4, 12, 13]. De Jongh et al. [4} conducted a randomized I/II ovarian cancer trial with
cisplatin and escalating doses of weekly or 4-weekly paclitaxel. The chemo-naïve patients
exhibited a 94% overall response rate and 48 month median overall survival, while
maintaining manageable toxicity. In a more recent advanced ovarian cancer study, Isonishi et
al. compared the impact of paclitaxel and carboplatin administered either tri-weekly (c-TC)
or dose dense weekly (dd-TC) with regard to patient progression free survival (PFS) [14].
Median PFS for the c-TC patients was 17.1 months and 27.9 months for the dd-TC group. There
was also more favorable survival rates in the dose dense patients (83.6%) in comparison to
the tri-weekly groups (77.7%)

Shen et al. conducted a Chinese study investigating the efficacy of combination weekly Taxol
plus Carboplatin compared to Taxol given every three weeks plus Carboplatin in previously
untreated ovarian cancer patients [12]. While the two regimens had equal efficacy, there was
less toxicity observed in the weekly regimen. Additional studies have also indicated that
lower doses and shorter infusion times inherent in weekly dosing regimens should mitigate
bone marrow myelosuppression and other toxicities associated with standard paclitaxel
3-weekly administration [13].

In addition to weekly primary induction chemotherapy regimens, studies involving
consolidation or maintenance therapy have been employed in the hopes of improving survival
[15, 16]. Micha et al. reported significantly better progression free survival results (94
weeks vs. 45 weeks) for an ovarian cancer group who received 12 cycles of paclitaxel
consolidation therapy following induction therapy, compared to a similar group who received
3 cycles of paclitaxel consolidation therapy [16].

The current pilot study was designed to determine toxicity, progression free survival, and
response rate of weekly Taxol; every four-week Carboplatin; and Vorinostat (7 days on, 7
days off 7 days on, 7 days off) given for 6 cycles. Some patients will continue on
consolidation therapy, which will consist of Taxol in combination with Vorinostat for an
additional 12 cycles.

Modifying the dosing schedule of established chemotherapy regimens using weekly chemotherapy
administration and consolidation therapy may decrease drug toxicity and maximize efficacy.
These benefits are particularly intriguing in patients for whom disease treatment is
long-term.

Since no triplet regimen has demonstrated compelling superiority, the combination of Taxol,
Carboplatin, and Vorinostat is intriguing because of their potential synergy, distinct
mechanisms of action, and non-overlapping toxicity.

Inclusion Criteria:

- Subjects with a histologic or cytologic diagnosis of stage III/IV ovarian cancer,
fallopian tube epithelial cancer, or peritoneal cancer who have not received prior
chemotherapy or radiotherapy.

- Subjects must have the appropriate surgery for their gynecologic cancer. However,
subjects may be treated in a neoadjuvant manner, with surgery being performed after
chemotherapy cycles 1, 2, or 3.

- If neoadjuvant therapy is not administered, subjects must receive their first dose no
more than six weeks postoperatively.

- Subjects must have adequate bone marrow, renal and hepatic function as defined by WBC
> 3,000 cells/cu ml., platelets > 100,000/cu.ml., calculated creatinine clearance >
50 ccs/min., bilirubin < 1.5 mg/dl, and SGOT < three times normal.

- Karnofsky performance status > 50%.

- Subjects who have signed an institutional review board (IRB) approved informed
consent form.

Exclusion Criteria:

- Subjects with epithelial ovarian cancer of low malignancy potential.

- Subjects with septicemia, severe infection, or acute hepatitis.

- Subjects with a history of congestive heart failure, angina, or a history of
myocardial infarction within the past six months.