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Protocol Details

Phase I Trial of Oral 5-Fluoro-2'-Deoxycytidine with Oral Tetrahydrouridine in Patients with Advanced Solid Tumors

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

12-C-0066

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: 120

Referral Letter Required

No

Population Exclusion(s)

Children;
Non-English Speaking

Special Instructions

Currently Not Provided

Keywords

DNA Methylation;
Advanced Cancer;
Methyltransferase Inhibitor;
Epigenetics;
Gene Re-Expression

Recruitment Keyword(s)

Cancer;
Solid Tumor

Condition(s)

Neoplasms

Investigational Drug(s)

FdCyd
THU

Investigational Device(s)

None

Intervention(s)

Drug: FdCyd + THU

Supporting Site

National Cancer Institute

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.

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Eligibility

INCLUSION CRITERIA:

-Patients must have histologically documented solid tumors whose disease has progressed on standard therapy that is known to be associated with a survival advantage or have disease for which there is no known standard therapy.

-Patients must have measurable or evaluable disease.

-Diagnosis of malignancy must be confirmed by the department of pathology at the institution where the patient is being enrolled prior to patient enrollment.

-Patients must have completed any chemotherapy, radiation therapy, biologic therapy, or major surgery greater than or equal to 4 weeks prior to enrollment (6 weeks for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a Phase 0 or equivalent study, at the discretion of the Principal Investigator. Patients must have recovered to eligibility levels from prior toxicity or adverse events. Patients with bone metastases or hypercalcemia on IV bisphosphonate treatment prior to study entry may continue this treatment.

-Age greater than or equal to18 years. Because no dosing or adverse event data are currently available on the use of FdCyd and THU in patients less than 18 years of age, children are excluded from this study, but may be eligible for future pediatric Phase I combination trials.

-Karnofsky performance status greater than or equal to 60%.

-Life expectancy of greater than 3 months.

-Patients must have normal organ and marrow function as defined below:

--absolute neutrophil count<TAB>greater than or equal to 1,500/mcL

--platelets<TAB><TAB><TAB>greater than or equal to 100,000/mcL

--total bilirubin<TAB><TAB>less than or equal to 1.5 X institutional upper limit of normal

--AST(SGOT)/ALT(SGPT)<TAB>greater than or equal to 3 X institutional upper limit of normal

--creatinine<TAB><TAB><TAB>less than 1.5 X institutional upper limit of normal

OR

--creatinine clearance<TAB><TAB>greater than or equal to 60 ML/min for patients with creatinine levels

<TAB><TAB><TAB><TAB>Above 1.5 X institutional upper limit of normal

-Because FdCyd has been shown to be teratogenic in animals, pregnant women are excluded from this trial. Nursing women are also excluded, as there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with FdCyd. Women of childbearing potential must agree to either abstain from sexual intercourse or use two forms of acceptable birth control, including one barrier method, for 4 weeks prior to study entry, for the duration of study participation, and for 3 months after completion of study. Men must use a latex condom every time they have sexual intercourse during therapy and for 3 months after study completion, even if they have had a successful vasectomy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she or her partner should inform the treating physician immediately.

-Ability to understand and the willingness to sign a written informed consent document.

-Patients should not be receiving any other investigational agents.

-Ability to swallow liquids.

-Willingness to provide blood and urine samples, and biopsy samples if on the expansion phase of the study, for research purposes. For the expansion cohort, patients must have tumor amenable to biospy (excisional or incision biopsies of skin or H & N lesions under visualization) and willingness to undergo a tumor biopsy or patient will be undergoing a procedure due to medical necessity during which the tissue may be collected, or tumor biopsy tissue from a previous research study or medical care is available for submission at registration. Criteria for the submission of tissue are:

--Tissue must have been collected within 3 months prior to registration

--Patient has not received any intervening therapy for their cancer since the collection of the tumor sample

--Tumor tissue must meet the minimum requirements

EXCLUSION CRITERIA:

-Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to active or uncontrolled infection, immune deficiencies, known HIV infection requiring protease inhibitor therapy, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

-Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 2 months after treatment of the brain metastases. Patients should be on stable doses of anti-seizure medications. These patients may be enrolled at the discretion of the Principal Investigator.

-History of allergic reactions attributed to fluoropyrimidines (e.g., capecitabine, fluorouracil, fluorodeoxyuridine) or tetrahydrouridine.

-Malabsorption syndrome or other conditions that would interfere with intestinal absorption.


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Citations:

Lapeyre JN, Becker FF. 5-Methylcytosine content of nuclear DNA during chemical hepatocarcinogenesis and in carcinomas which result. Biochem Biophys Res Commun. 1979 Apr 13;87(3):698-705.

Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003 Nov 20;349(21):2042-54.

Daniel FI, Cherubini K, Yurgel LS, de Figueiredo MA, Salum FG. The role of epigenetic transcription repression and DNA methyltransferases in cancer. Cancer. 2011 Feb 15;117(4):677-87. doi: 10.1002/cncr.25482. Epub 2010 Oct 13.

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Contacts:

Principal Investigator

Referral Contact

For more information:

James H. Doroshow, M.D.
National Cancer Institute (NCI)
BG 31 RM 3A44
31 CENTER DR
BETHESDA MD 20814
(301) 496-4291
doroshoj@mail.nih.gov

Jennifer H. Zlott
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 12N226
10 Center Drive
Bethesda, Maryland 20892
(301) 435-5664
zlottjh@mail.nih.gov

Michelle Eugeni, R.N.
National Institutes of Health
Building 10
Room 3-5667
10 Center Drive
Bethesda, Maryland 20892
(301) 594-4325
meugeni@mail.nih.gov

Clinical Trials Number:

NCT01534598

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