Vorinostat, Carboplatin and Gemcitabine Plus Vorinostat Maintenance in Women With Recurrent, Platinum-Sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

Condition(s) targeted: Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer

Intervention: Vorinostat (Drug); Carboplatin (Device); Gemcitabine (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Dana-Farber Cancer Institute

Official(s) and/or principal investigator(s):
Ursula A. Matulonis, MD, Principal Investigator, Affiliation: Dana-Farber Cancer Institute

Overall contact:
Ursula A. Matulonis, MD, Phone: 617-632-2334

The purpose of this research study is to: 1) Determine the highest dose of the drug vorinostat that can be given safely in combination with carboplatin and gemcitabine and 2) determine how long the participant's cancer will respond to the combination of vorinostat, carboplatin and gemcitabine. Vorinostat is a type of drug called a histone deacetylase inhibitor (HDAC inhibitor). HDAC inhibitors interact with chromosomes in the cancer cell and cause cancer cells to stop growing. Vorinostat has shown a decrease in the amount of ovarian cancer cells growing in the laboratory and also may enhance the anti-cancer effects of carboplatin.

Official title: Phase IB/II Study of Combination Vorinostat, Carboplatin and Gemcitabine Plus Vorinostat Maintenance in Women With Recurrent, Platinum-Sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

Study design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study

Primary outcome:

Determine the maximally tolerated dose (MTD) of vorinostat when combined with fixed dose, standard carboplatin/gemcitabine in patients wtih recurrent platinum-sensitive epithelial ovarian cancer.

Estimate the median progression-free survival (PFS) for this population in a phase II expansion cohort of patients treated with carboplatin/vorinostat and vorinostat maintenance.

Secondary outcome:

Estimate the response rate of vorinostat plus carboplatin/gemcitabine via GCIG CA125 criteria or via RECIST criteria in this patient population.

Assess the toxicities of carboplatin/gemcitabine plus vorinostat

Measure the overall survival (OS) and progression-free survival and progression-free survival (PFS) in this patient population

Detailed description:

- We are looking for the highest dose of the study drug that can be administered safely

without severe or unmanageable side effects. Not everyone who participates in this research study will receive the same dose of the study drug, vorinostat. The dose you get will depend on the number of participants who have been enrolled in the study before you and how well they have tolerated their doses. There are 3 dose levels for vorinostat that are being tested.

- Each treatment cycle lasts three weeks or 21 days. The carboplatin and gemcitabine

chemotherapy will be administered as per the FDA approved doses. The carboplatin will be administered on day 1 through the vein and gemcitabine will be administered intravenously on day 1 and day 8. Participants will receive up to 8 cycles of chemotherapy, as determined by the participant and their doctor, depending on how well the cancer is responding and what side effects the participant is experiencing.

- Participants will take the study medication, vorinostat, by mouth, once a day in the

morning beginning on day 1 of the cycle. Participants will take the vorinostat for the first two weeks (14 days) of each cycle. The 3rd week of the cycle, participants will not take the study drug vorinostat.

- Physical exams will be performed regularly while participants are on this study.

- Participants cancer will be assessed during treatment while on this study. If

participants CA125 value is elevated, we will follow the cancer by the CA125 blood test every 2 cycles. If the cancer is only visible on CT or MRI scan and the CA125 blood test is not elevated, regular assessment of the cancer (every 2 cycles of chemotherapy) by CT or MRI scan will also occur. Once the chemotherapy has been completed, a CT or MRI scan will be performed on all participants to determine if they are eligible to continue on the study and receive vorinostat maintenance.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

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

Ursula A. Matulonis, MD, Phone: 617-632-2334

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States; Recruiting
Ursula A. Matulonis, MD, Principal Investigator

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Recruiting
Richard T. Penson, MD, Principal Investigator

Starting date: June 2009
Last updated: June 29, 2009