FdCyd and THU for Advanced Solid Tumors

Neoplasms Clinical Trial

Official title: Phase I Trial of Oral 5-Fluoro-2'-Deoxycytidine With Oral Tetrahydrouridine in Patients With Advanced Solid Tumors

Status Completed

Clinical Trial Summary

Background:

• 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.

Objectives:

• To test oral FdCyd and THU on advanced solid tumors that have not responded to earlier treatments.

Eligibility:

• Individuals at least 18 years of age who have advanced solid tumors that have not responded to standard treatments.

Design:

• 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.

Clinical Trial 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, co-administration 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.

Primary objectives:

-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

Exploratory objectives:

• Determine the pharmacokinetics of oral FdCyd and oral THU

• Document preliminary evidence of activity of oral FdCyd and oral THU

• Determine the clinical benefit rate (CR+PR+SD at 4 months) in patients treated with study drug combination at the MTD

• Determine effect of study treatment on re-expression of p16 and other select genes silenced by methylation in circulating tumor cells and tumor biopsies

• Evaluate the effect of study treatment on DNA (cytosine-5)-methyltransferase 1 and 3 (DNMT1 and DNMT3) expression in tumor biopsies

Eligibility:

-Adults with histologically documented solid tumors whose disease has progressed after at least one line of standard therapy.

Design:

• 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 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.

• Up to 25 patients will be enrolled in the expansion cohort, from which mandatory pre- and post-dose tumor biopsies will be collected for the assessment of pharmacodynamic endpoints, at dose level 8 (160 mg FdCyd + 3000 mg THU 1x daily days 1-6 week 1, days 8-13 week 2, in 21-day cycles). ;

Related Conditions & MeSH terms

• Neoplasms

• NCT number: NCT01534598
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: March 5, 2012
• Completion date: February 19, 2020