FdCyd and THU for Advanced Solid Tumors
- FdCyd (also called 5-fluoro-2'-deoxycytidine) and THU (also called tetrahydrouridine) are experimental cancer treatment drugs. FdCyd may change how genes work in cancer cells. THU helps keep FdCyd from being broken down by the body. FdCyd and THU have been given to people on other cancer treatment trials, usually by vein. Researchers want to give FdCyd and THU by mouth to see if they work against cancers that have not responded to earlier treatments.
- To test oral FdCyd and THU on advanced solid tumors that have not responded to earlier treatments.
- Individuals at least 18 years of age who have advanced solid tumors that have not responded to standard treatments.
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor samples will used to study the cancer before treatment.
- FdCyd and THU will be given in 21-day cycles. THU should be taken 30 minutes before taking FdCyd.
- Participants will take FdCyd and THU by mouth, once a day, for 3 days at the beginning of the first and second weeks of each cycle (days 1 3 and 8 10). The drugs will not be taken during the entire third week of each cycle.
- Treatment will be monitored with frequent blood tests and imaging studies.
- Treatment will continue as long as the cancer is responding to the drugs and serious side effects do not develop....
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Trial of Oral 5-Fluoro-2-Deoxycytidine With Oral Tetrahydrouridine in Patients With Advanced Solid Tumors|
- Establish the safety and tolerability of oral FdCyd in combination with oral THU administered on an intermittent schedule of 3 days/week for 2 weeks on treatment, then 1 week off, in 21-day cycles to patients with refractory solid tumors
- Determine PK of oral FdCyd and oral THU
- Document preliminary evidence of activity
- Determine effect on re-expression of select genes silenced by methylation in circulating cells
|Study Start Date:||January 2012|
|Estimated Study Completion Date:||September 2014|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
- 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 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 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.
- Intravenous FdCyd with THU has been evaluated in a Phase I clinical trial with some preliminary evidence of activity. This trial will investigate oral administration of the drugs, which was shown to be feasible in an expansion cohort of the previous trial.
- Establish the safety and tolerability of oral FdCyd in combination with oral THU administered on an intermittent schedule in 21-day cycles to patients with refractory solid tumors
- Determine the pharmacokinetics of oral FdCyd and oral THU
- Document preliminary evidence of activity of oral FdCyd and oral THU
- Determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cells
- Determine the clinical benefit rate (CR plus PR plus SD at 4 months) in patients treated with study drug combination at the MTD.
-Adults with histologically documented solid tumors whose disease has progressed after at least one line of standard therapy.
Please note: As of 02/13, we have received and reviewed PK data through dose level 4. PK data show that the target Cmax has been achieved; therefore, following enrollment to DL5 (160 mg for 3 days/week for 2 out of 3 weeks) we are increasing the number of days of administration of FdCyd with THU per dose escalation table below per Amendment C dated 05/22/2013.
- This is a multicenter trial with NCI as the coordinating center.
- FdCyd and THU will be administered on an intermittent schedule in 21-day cycles. THU will be administered orally at a fixed dose of 3000 mg 30 minutes prior to FdCyd.
- The trial will follow a standard Phase I dose escalation design (3-6 patients per cohort).
- Consideration will be given to increasing the days of administration of FdCyd with THU after a target maximum plasma concentration of FdCyd is reached.
- Blood and urine for pharmacokinetic studies will be obtained from all patients. Blood for
pharmacodynamic studies will be obtained after we achieve a target Cmax of 1microM.
|Contact: Michelle Eugeni, R.N.||(301) firstname.lastname@example.org|
|Contact: James H Doroshow, M.D.||(301) email@example.com|
|United States, California|
|University of California, Davis||Recruiting|
|Davis, California, United States, 95616|
|University of Southern California Health Sciences Campus||Recruiting|
|Los Angeles, California, United States, 90033|
|Contact: James Doroshow, M.D. 301-496-4916 firstname.lastname@example.org|
|City of Hope Medical Group||Recruiting|
|South Pasadena, California, United States, 91030|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937|
|United States, Pennsylvania|
|Penn State Hershey Cancer Institute||Recruiting|
|Hershey, Pennsylvania, United States|
|University of Pittsburgh Cancer Center||Recruiting|
|Pittsburgh, Pennsylvania, United States|
|Principal Investigator:||James H Doroshow, M.D.||National Cancer Institute (NCI)|