Phase I Trial of Oral 5-Fluoro-2-Deoxycytidine With Oral Tetrahydrouridine in Patients With Advanced Solid Tumors
- 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
- 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
- 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
- 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
pharmacodynamic studies will be obtained after we achieve a target Cmax of 1microM.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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
James H Doroshow, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|City of Hope Medical Group||Pasadena, California 91105|
|University of Pittsburgh Cancer Center||Pittsburgh, Pennsylvania 15232|
|University of California, Davis||Sacramento, California 95818|
|Penn State Hershey Cancer Institute||Hershey, Pennsylvania 17033|
|University of Southern California Health Sciences Campus||Los Angeles, California 90033|
|Comprehensive Cancer Center||Madison, Wisconsin|