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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Neoplasms

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Trial Information

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


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 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.

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

- 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.

Eligibility:

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

Design:

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.

Inclusion Criteria


- 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 greater than or equal to 1,500/mcL

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

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

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

- creatinine less than 1.5 X institutional upper limit of normal

OR

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

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 for research purposes.

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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Principal Investigator

James H Doroshow, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

120066

NCT ID:

NCT01534598

Start Date:

January 2012

Completion Date:

September 2013

Related Keywords:

  • Neoplasms
  • DNA Methylation
  • Advanced Cancer
  • Methyltransferase Inhibitor
  • Epigenetics
  • Gene Re-Expression
  • Cancer
  • Solid Tumor
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
City of Hope Medical GroupPasadena, California  91105
University of Pittsburgh Cancer CenterPittsburgh, Pennsylvania  15232
University of California, DavisSacramento, California  95818
Penn State Hershey Cancer InstituteHershey, Pennsylvania  17033
University of Southern California Health Sciences CampusLos Angeles, California  90033
Comprehensive Cancer CenterMadison, Wisconsin