Vorinostat, Carboplatin and Gemcitabine in Women With Recurrent, Platinum-Sensitive Ovarian Cancer

OBJECTIVES:

Primary

Phase Ib: Determine the maximally tolerated dose (MTD) of vorinostat when used in combination
with standard (fixed) doses of carboplatin/gemcitabine during a 21 day cycle in patients with
recurrent platinum-sensitive ovarian cancer

Phase II: Estimate the median progression-free survival (PFS) of patients treated with
carboplatin/gemcitabine/vorinostat and vorinostat maintenance

Secondary

- Estimate the response rate of carboplatin/gemcitabine/vorinostat

- Assess the toxicities of carboplatin/gemcitabine/vorinostat

- Assess the toxicities of maintenance vorinostat

- Measure overall survival (OS) and progression-free survival (PFS)

STATISTICAL DESIGN:

The Phase Ib study was originally design to follow a standard 3+3 dose escalation design and
evaluate 4 vorinostat dose levels.The DLT observation period was the 21-day cycle 1 length.
Note: Ultimately 6 dose levels were evaluated as the protocol was amended to add dose levels,
de-escalating cumulative vorinostat dose per cycle when 2 of 3 participants in dose level
cohorts 2A, 1B and 1C experienced DLTs.

In the Phase II study, a median PFS of 13 months would be worthy of further study,
representing a 66% improvement compared with the historical median of 8.6 months observed
with carboplatin/gemcitabine. With 36 evaluable patients, there is 80% power to reject the
null hypothesis in favor of the alternative at a 5% significance level.

Inclusion Criteria:

- Histologically confirmed recurrent epithelial ovarian cancer, fallopian tube cancer,
or peritoneal cancer

- Must have received a platinum-based chemotherapy regimen at initial diagnosis

- Patients with primary platinum-sensitive (defined as a cancer initially
platinum-sensitive followed by a progression-free interval from first exposure to
platinum of 6 months or greater) recurrent ovarian, tubal or peritoneal cancer

- Must have an elevated CA125 (twice the ULN) within 2 weeks of enrolling on study (2
pretreatment measurements that are twice the upper limits of institutional normal and
are drawn at least 1 day but not more than 14 days apart). At least one of the samples
should be checked within one week of starting treatment. Measurable cancer via RECIST
criteria via CT or MRI scan is not required but if clinically indicated will be
monitored.

- For patients who do not have an elevated CA125 (twice the ULN), participants must have
measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded) as 20mm or greater with
conventional techniques or as 10mm or greater with spiral CT scan.

- 18 years of age or older

- Life expectancy of greater than 16 weeks

- ECOG Performance Status 0, 1, or 2

- Participants must have normal organ and marrow function as outlined in the protocol

- Patients could have received up to 1 prior non-platinum chemotherapy regimen in the
recurrent setting (anti-angiogenic agents and other phase II non-hormonal therapies
used to treat recurrent cancer count as a prior non-platinum therapy) but only one
prior platinum (used to treat initial diagnosis). Patients may received up to 2 prior
hormonal therapies.

- Women of child-bearing potential must agree to use adequate contraception prior to
study entry and for the duration of study participation

- Must be able and willing to take oral medications

- No clinical nor radiographic evidence of an existing or impending bowel obstruction

- Should be at least 2 weeks from any surgical procedure, with the exception of minor
surgery, such as port placement

- Patients who have known carboplatin hypersensitivity reaction can receive carboplatin
if they are followed by an allergist, follow a published hypersensitivity
desensitization protocol when receiving carboplatin, and agree to receive carboplatin
under these circumstances

- Patients taking valproic acid for epilepsy may enroll if they discontinue valproic
acid 30 days prior to enrolling for washout

- Patients must have a normal QTc interval and no history of QTc prolongation on EKG

Exclusion Criteria:

- Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C)
prior to entering the study or those who have not recovered from adverse events due to
agents administered more than 4 weeks earlier

- May not be receiving any other investigational agent

- Participants with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, pulmonary disease, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- Pregnant or breastfeeding women

- Individuals with a history of different malignancy are ineligible except for the
following circumstances: disease-free for at least 5 years and are deemed by the
investigator to be a low risk for recurrence of that malignancy; cervical cancer in
situ, concurrent stage IA and grade I endometrial cancer, and basal cell or squamous
cell carcinoma of the skin

- Patients taking valproic acid unless valproic acid is stopped at least 30 days prior
to enrollment

- Receipt in the past of any other HDAC inhibitor for treatment of any malignancy

- Receipt of radiation therapy to >25% of bone marrow-bearing areas

- Patients who have gastrointestinal disorders likely to interfere with absorption of
vorinostat

- Known active HIV or hepatitis viral infection