Trial of Decitabine as a Sensitizer to Carboplatin in Platinum Resistant Recurrent Ovarian Cancer
Based on these pre-clinical data, which were generated by our group, the investigators propose to test in a phase I/II clinical trial the following hypothesis: demethylation induced by decitabine results in re-sensitization to platinum in recurrent ovarian cancer.
To test this hypothesis, the investigators will treat patients with recurrent ovarian cancer platinum resistant (recurrence within 6 months from platinum therapy) or platinum-refractory (no response to platinum) with a combination consisting of decitabine and carboplatin.
This will be an institutional open label phase I/II trial to determine the safety and the biologic activity of the Decitabine/Carboplatin combination.
The investigators will determine whether Carboplatin can be safely combined with Decitabine, the optimal dose schedule and the investigators will define whether at this dosage, the regimen is biologically active (i.e. induces demethylation of target genes).
In the second part of the trial, the investigators will determine the clinical activity of the combination in a population of patients with platinum-resistant ovarian cancer.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Trial of Decitabine as a Sensitizer to Carboplatin in Platinum Resistant Recurrent Ovarian Cancer|
- Phase I: Maximum Tolerated Dose (MTD) for Use in Phase II [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]The definition of MTD will follow the standard definition of the phase I 3+3 trial concept. Dose Limiting Toxicities (DLTs) will be scored in the first cycle. Patients will be monitored for 28 days (a cycle) to determine whether a DLT is experienced for the specific dose level.
- Phase II: Percent of Patients With Objective Response [ Time Frame: screening until end of study (approx 12-18 months) ] [ Designated as safety issue: No ]The percent of patients having an objective response (Complete Response or Partial Response) will be estimated with a 95% exact binomial confidence interval for the percent of patients receiving drug.
- Phase II: Percent of Patients With Objective Response, CA125 Response or Stable Disease > 3 Months [ Time Frame: screening until end of study (approx 12-18 months) ] [ Designated as safety issue: No ]The percent of patients having an objective response (Complete Response or Partial Response) or CA125 response (Complete Response or Partial Response) or stable disease > 3 months will be estimated with a 95% exact binomial confidence interval for the percent of patients receiving drug.
- Phase II: Progression Free Survival [ Time Frame: Baseline until disease progression or last visit ] [ Designated as safety issue: No ]Progression free survival times will be estimated using the Kaplan-Meier method. If a patient progresses or dies, the time till that event will be used. If a patient does not progress or die on the study, the patient will be censored at the last available visit. Confidence intervals on the median will be constructed.
|Study Start Date:||July 2007|
|Study Completion Date:||September 2013|
|Primary Completion Date:||May 2011 (Final data collection date for primary outcome measure)|
Experimental: Carboplatin combined with Decitabine
Decitabine at escalating dose levels will be given X 5 days followed by Carboplatin given on Day 8.
Decitabine dose will be escalated as follows.
Dose level 1: 10mg/m2 IV QD X 5 days Dose level 2: 20mg/m2 IV QD X 5 days Dose level -1: Carboplatin AUC 4.
Decitabine at escalating dose levels will be given IV X 5 days followed by Carboplatin given IV on Day 8 at a dose corresponding to an area under curve (AUC) of 5. The maximum dose of Decitabine (20 mg/m2) is based on the results of the myelodysplastic syndrome (MDS) clinical trial that demonstrated biological and clinical efficacy at this dose (15-17). It is recognized that higher doses of decitabine can be administered, myelotoxicity being the most significant adverse event. This protocol will assess the lower less toxic but biologically active dose.
Decitabine dose will be escalated as follows.
Dose level -1: 5 mg/m2 IV per day (QD) X 5 days Dose level 1: 10mg/m2 IV QD X 5 days Dose level 2: 20mg/m2 IV QD X 5 days
Each cycle will consist of 28 days, with delays to allow blood count recovery. Correlative blood draws will occur on Day1 (baseline) and on Day 8 before Carboplatin for cycle 1 and 2.
The escalation phase will follow the standard 3+3 design. That is, patients will be accrued to each dose level in cohorts of up to 3-6 patients. Escalation will continue until a DLT is observed, the highest dose-level is reached, or medical judgment indicates. The goal of the phase I cohort is to ensure the safety and tolerability of the combination, not to define the maximum tolerated dose.
An initial 3 patients will be enrolled at dose level 1. If all 3 patients in dose level 1 complete 4 weeks of therapy without dose limiting toxicity (DLT), the study will proceed to enroll 3 patients at dose level 2. If all 3 patients in dose level 2 complete 4 weeks of therapy without DLT, we will accrue 3 more to ensure that only 0 or 1 of 6 have a DLT and then proceed to the phase II cohort. As dose level 2 represents full doses of both agents, there will be no further dose escalation beyond dose level 2.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00477386
|United States, Indiana|
|Indiana University Cancer Center|
|Indianapolis, Indiana, United States, 46202|
|Principal Investigator:||Daniela Matei, MD||Indiana University|