A Multi-Histology Phase II Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)
- Conditions
- Head and Neck NeoplasmsUrinary Bladder NeoplasmsLung NeoplasmsBreast Neoplasms
- Interventions
- Registration Number
- NCT00978250
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
* Two experimental drugs, FdCyd (also called 5-fluoro-2'-deoxcytidine), and THU (also called tetrahydrouridine), are undergoing trials to test their effectiveness in treating cancer that has not responded to standard therapies. FdCyd is thought to work by changing how genes work in cancer cells. THU does not have any anticancer effects on its own, but it helps keep the other drug, FdCyd, from being broken down by the body.
* These drugs are being tested in several separate clinical trials.
Objectives:
* To determine if FdCyd and THU can work together to control tumor growth.
* To evaluate the safety and tolerability of FdCyd and THU when given together.
Eligibility:
- Individuals 18 years of age and older who have advanced non-small cell lung cancer, breast cancer, bladder cancer, or head and neck cancer that has progressed after receiving standard treatment or for which no effective therapy exists.
Design:
* The drugs are given over 28-day periods called cycles. FdCyd and THU are given through a vein for about 3 hours each day on days 1, 5 and 8, 12 of each cycle.
* Clinical Center visits: FdCyd and THU will be given through a vein on days 1, 5 and 8, 12 of each cycle. During the Clinical Center visits, researchers will perform study tests and procedures to see how the study drugs are affecting the body.
* Patients will undergo a number of tests and procedures during the treatment cycle, including physical examinations, blood and urine samples for standard tests, imaging studies (ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scans) to evaluate tumor growth, and blood and urine samples to evaluate the amount of FdCyd and THU in the body and the body's response to the drugs.
* Patients may continue to receive FdCyd and THU if their cancer does not grow, if they do not have too many side effects, and if they are willing to do so.
- Detailed Description
Background:
5-Fluoro-2'-deoxycytidine (FdCyd), a fluoropyrimidine nucleoside analog, has a short (10-minute) half-life and is rapidly degraded in vivo by cytidine deaminase. However, coadministration with tetrahydrouridine (THU), an inhibitor of cytidine/deoxycytidine deaminase, has been shown to increase the area under the curve (AUC) of the parent compound more than 4-fold. Increased FdCyd exposure allows it to be taken up intracellularly and converted to its triphosphate, which is incorporated into deoxyribonucleic acid (DNA) and inhibits the action of the enzyme DNA methyltransferase (DNMT). Inhibition of DNMT, and in turn DNA methylation, can result in the re-expression of tumor suppressor genes.
Primary objective:
-Determine progression-free survival (PFS) and/or the response rate (Complete Response (CR) + Partial Response (PR)) of FdCyd administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over 3 hours along with THU in patients with breast cancer, head and neck cancer, non-small cell lung cancer (NSCLC), and urothelial transitional cell carcinoma.
Exploratory objectives:
* Evaluate whether treatment with FdCyd and THU alters DNA methylation patterns in tumor biopsy samples before and during treatment by long interspersed nuclear element-1 (LINE-1) analysis.
* Evaluate the safety and tolerability of FdCyd (100 mg/m(2)) + THU (350 mg/m(2)) administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over 3 hours.
* Measure changes in the number of circulating tumor cells (CTCs) following treatment with FdCyd plus THU.
Eligibility:
-Patients with histologically documented non-small cell lung cancer, head and neck cancer, urothelial transitional cell carcinoma, and breast carcinoma.
Design:
* This is a multicenter trial with National Cancer Institute (NCI) as the coordinating center and the California Cancer Consortium and University of Pittsburgh Medical Center (UPMC) as participating sites.
* FdCyd will be administered as an intravenous (IV) infusion over 3 hours with 20% of the daily dose of THU administered as an IV push and the remaining 80% co-administered with FdCyd by 3-hour infusion daily for 5 consecutive days of treatment per week for 2 consecutive weeks, followed by 2 weeks of no treatment, in a 28-day cycle.
* Blood and optional tumor biopsies for pharmacodynamic and pharmacokinetic studies will be obtained.
* The study will accrue a maximum of 165 patients including all centers.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 95
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 5-Fluro-2'-Deoxycytidine (FdCyd) + Tetrahydrouridine (THU) 5-Fluoro-2'-Deoxycytidine (FdCyd) + Tetrahydrouridine (THU) FdCyd (100 mg/m(2)) + THU (350 mg/m(2)) administered 5 days/week for 2 weeks in 28-day cycles
- Primary Outcome Measures
Name Time Method Percentage of Participants With (Complete Response (CR) + Partial Response (PR)) to 5-Fluro-2'-Deoxycytidine (FdCyd) until subject progressed or went off study for other reasons (up to approximately 1 year) Response was measured using the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of the LD.
Progression-free Survival (PFS) until subject progressed or went off study for other reasons (up to approximately 1 year) Progression-free survival (PFS) is defined as the time interval from start of treatment to documented evidence of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since the treatment started or the appearance of one or more new lesions.
- Secondary Outcome Measures
Name Time Method Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). Date treatment consent signed to date off study, approximately 109 months and 16 days. Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Trial Locations
- Locations (4)
City of Hope National Medical Center
🇺🇸Duarte, California, United States
University of California, Davis
🇺🇸Davis, California, United States
City of Hope Medical Group
🇺🇸South Pasadena, California, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States