Clinical trial NCT00910000
Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: carboplatin gemcitabine vorinostat
Sponsor: Dana-Farber Cancer Institute
Start date: 2009-06-01; Completion date: 2015-10-01
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This trial is a Phase Ib/II study of carboplatin/gemcitabine/vorinostat for the treatment of platinum sensitive recurrent ovarian cancer. The carboplatin and gemcitabine combination is an FDA approved regimen for platinum-sensitive recurrent ovarian cancer. 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.The purpose of the Phase Ib study is to determine the highest dose of the drug vorinostat that can be given safely in combination with carboplatin and gemcitabine. Not everyone who participates in this research study will receive the same dose of the study drug, vorinostat, but carboplatin and gemcitabine doses are held constant. Vorinostat doses depend on previous enrollment and tolerability. The expansion Phase II study uses the vorinostat dose found in the Phase Ib study in combination with carboplatin/gemcitabine and as a single agent maintenance therapy to better understand toxicity and efficacy.

Detailed description:
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.

Arms: arm 1: Vorinostat: 200 mg taken orally once a day for the first two weeks of each three-week cycle

Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle

Gemcitabine: 100 mg/m2, given intravenously on day 1 and day 8 of every three week cycle

Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision. arm 2: Vorinostat: 300mg, taken orally once a day for the first two weeks of each three-week cycle

Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle

Gemcitabine: 1000 mg/m2, given intravenously on day 1 and day 8 of every three week cycle

Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision. arm 3: Vorinostat: 200mg, taken orally twice a day for days 1-3 and days 8-10 of every three week cycle

Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle

Gemcitabine: 1000 mg/m2, given intravenously on day 1 and day 8 of every three week cycle

Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision. arm 4: Vorinostat: 200mg, taken orally twice a day for days 1, 2, 8 and 9 of every three week cycle

Carboplatin: AUC 4, given intravenously on day 2 of every three week cycle

Gemcitabine: 1000 mg/m2, given intravenously on day 2 and day 9 of every three week cycle

Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision. arm 5: Vorinostat: 300mg, taken orally once a day for days 1 and 2 of every three week cycle

Carboplatin: AUC 4, given intravenously on day 2 of every three week cycle

Gemcitabine: 1000 mg/m2, given intravenously on day 2 and day 9 of every three week cycle

Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision. arm 6: Vorinostat: 400mg, taken orally once a day for days 1 and 2 of every three week cycle

Carboplatin: AUC 4, given intravenously on day 2 of every three week cycle

Gemcitabine: 1000 mg/m2, given intravenously on day 2 and day 9 of every three week cycle

Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.
Interventions: intervention 1: Vorinostat intervention 2: Carboplatin intervention 3: Gemcitabine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents: