A Multi-Histology Phase II Study of 5-Fluoro-2-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)

ID: NCT00978250
Status: Recruiting
Phase: Phase 2
Start Date: August 20, 2009
First Submitted: September 15, 2009
Last Updated: February 23, 2018
Results: N/A
Sponsors & Collaborators: National Cancer Institute (NCI)
Location: United States
Conditions: Head and Neck Neoplasms, Lung Neoplasms, Urinary Bladder Neoplasms, Breast Neoplasms
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Study Description

Brief Summary

Background:

- Two experimental drugs, FdCyd (also called 5-fluoro-2'-deoxcytidine), and THU (also called tetrahydrouridine), are undergoing trials to test their effectiveness in treating cancer that has not responded to standard therapies. FdCyd is thought to work by changing how genes work in cancer cells. THU does not have any anticancer effects on its own, but it helps keep the other drug, FdCyd, from being broken down by the body.

- These drugs are being tested on several separate clinical trials.

Objectives:

- To determine if FdCyd and THU can work together to control tumor growth.

- To evaluate the safety and tolerability of FdCyd and THU when given together.

Eligibility:

- Individuals 18 years of age and older who have advanced non-small cell lung cancer, breast cancer, bladder cancer, or head or neck cancer that has progressed after receiving standard treatment or for which no effective therapy exists.

Design:

- The drugs are given over 28-day periods called cycles. FdCyd and THU are given through a vein for about 3 hours each day on days 1 5 and 8 12 of each cycle.

- Clinical Center visits: FdCyd and THU will be given through a vein each day on days 1 5 and 8 12 of each cycle. During the Clinical Center visits, researchers will perform study tests and procedures to see how the study drugs are affecting the body.

- Patients will undergo a number of tests and procedures during the treatment cycle, including physical examinations, blood and urine samples for standard tests, imaging studies (ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scans) to evaluate tumor growth, and blood and urine samples to evaluate the amount of FdCyd and THU in the body and the body's response to the drugs.

- Patients may continue to receive FdCyd and THU if their cancer does not grow, if they do not have too many side effects, and if they are willing to do so.

Detailed 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, 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.

Objectives:

- Determine progression-free survival (PFS) and/or the response rate (CR + PR) of FdCyd administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over 3 hours along with THU in patients with breast cancer, head and neck cancer, non-small cell lung cancer, and urothelial transitional cell carcinoma.

- Evaluate whether treatment with FdCyd and THU alters DNA methylation patterns in tumor biopsy samples before and during treatment by LINE-1 analysis.

- Evaluate the safety and tolerability of FdCyd (100 mg/m(2)) + THU (350 mg/m(2)) administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over 3 hours.

- Measure changes in the number of CTCs following treatment with FdCyd plus THU.

Eligibility:

-Patients with histologically documented non-small cell lung cancer, head and neck cancer, urothelial transitional cell carcinoma, and breast carcinoma.

Design:

- This is a multicenter trial with NCI as the coordinating center and the California Cancer Consortium and UPMC as participating sites.

- FdCyd will be administered as an IV infusion over 3 hours with 20% of the daily dose of THU administered as an IV push and the remaining 80% co-administered with FdCyd by 3-hour infusion daily for 5 consecutive days of treatment per week for 2 consecutive weeks, followed by 2 weeks of no treatment, in a 28-day cycle.

- Blood and optional tumor biopsies for pharmacodynamic and pharmacokinetic studies will be obtained.

- The study will accrue a maximum of 165 patients including all centers.
Condition or disease Intervention/treatment Phase

Breast Neoplasms

Head and Neck Neoplasms

Lung Neoplasms

Urinary Bladder Neoplasms

Drug: 5-Fluoro-2-Deoxycytidine (FdCyd)
Other Names
Drug: Tetrahydrouridine (THU)
Other Names
Phase 2

Tracking Information

First Submitted DateSeptember 15, 2009
Last Update Posted DateFebruary 23, 2018
Start DateAugust 20, 2009
Anticipated Completion DateJune 02, 2020
Primary Completion DateMay 27, 2019
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Determine progression-free survival (PFS) and/or the response rate(CR + PR) of FdCyd [Time Frame: 4 or 6 months]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Evaluate whether treatment with FdCyd and THU alters DNA methylation patterns in [Time Frame: 2 Cycles]

  • Evaluate the safety and tolerability of FdCyd (100 mg/m2) + THU (350 mg/m2) [Time Frame: 1 Cycle]

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleA Multi-Histology Phase II Study of 5-Fluoro-2-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)
Official TitleA Multi-Histology Phase II Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)
Brief Summary

Background:

- Two experimental drugs, FdCyd (also called 5-fluoro-2'-deoxcytidine), and THU (also called tetrahydrouridine), are undergoing trials to test their effectiveness in treating cancer that has not responded to standard therapies. FdCyd is thought to work by changing how genes work in cancer cells. THU does not have any anticancer effects on its own, but it helps keep the other drug, FdCyd, from being broken down by the body.

- These drugs are being tested on several separate clinical trials.

Objectives:

- To determine if FdCyd and THU can work together to control tumor growth.

- To evaluate the safety and tolerability of FdCyd and THU when given together.

Eligibility:

- Individuals 18 years of age and older who have advanced non-small cell lung cancer, breast cancer, bladder cancer, or head or neck cancer that has progressed after receiving standard treatment or for which no effective therapy exists.

Design:

- The drugs are given over 28-day periods called cycles. FdCyd and THU are given through a vein for about 3 hours each day on days 1 5 and 8 12 of each cycle.

- Clinical Center visits: FdCyd and THU will be given through a vein each day on days 1 5 and 8 12 of each cycle. During the Clinical Center visits, researchers will perform study tests and procedures to see how the study drugs are affecting the body.

- Patients will undergo a number of tests and procedures during the treatment cycle, including physical examinations, blood and urine samples for standard tests, imaging studies (ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scans) to evaluate tumor growth, and blood and urine samples to evaluate the amount of FdCyd and THU in the body and the body's response to the drugs.

- Patients may continue to receive FdCyd and THU if their cancer does not grow, if they do not have too many side effects, and if they are willing to do so.

Detailed 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, 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.

Objectives:

- Determine progression-free survival (PFS) and/or the response rate (CR + PR) of FdCyd administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over 3 hours along with THU in patients with breast cancer, head and neck cancer, non-small cell lung cancer, and urothelial transitional cell carcinoma.

- Evaluate whether treatment with FdCyd and THU alters DNA methylation patterns in tumor biopsy samples before and during treatment by LINE-1 analysis.

- Evaluate the safety and tolerability of FdCyd (100 mg/m(2)) + THU (350 mg/m(2)) administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over 3 hours.

- Measure changes in the number of CTCs following treatment with FdCyd plus THU.

Eligibility:

-Patients with histologically documented non-small cell lung cancer, head and neck cancer, urothelial transitional cell carcinoma, and breast carcinoma.

Design:

- This is a multicenter trial with NCI as the coordinating center and the California Cancer Consortium and UPMC as participating sites.

- FdCyd will be administered as an IV infusion over 3 hours with 20% of the daily dose of THU administered as an IV push and the remaining 80% co-administered with FdCyd by 3-hour infusion daily for 5 consecutive days of treatment per week for 2 consecutive weeks, followed by 2 weeks of no treatment, in a 28-day cycle.

- Blood and optional tumor biopsies for pharmacodynamic and pharmacokinetic studies will be obtained.

- The study will accrue a maximum of 165 patients including all centers.

Study TypeInterventional
Study PhasePhase 2
Estimated Enrollment
165
Allocation
Not Available
Interventional Model
Single Group Assignment
Masking
None (Open Label)
Primary Purpose
Treatment
Conditions
Breast Neoplasms
Head and Neck Neoplasms
Lung Neoplasms
Urinary Bladder Neoplasms
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: 5-Fluoro-2-Deoxycytidine (FdCyd)

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 THU, an inhibitor of cytidine/deoxycytidine deaminase, has been shown to increase the AUC of the pare 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 DNM and in turn DNA methylation,can result in the re-expression of tumor suppressor genes.

Other Names
Drug: Tetrahydrouridine (THU)

Other Names
Study Groups/Cohorts
1
FdCyd (100 mg/m2) + THU (350 mg/m2) administered 5 days/week for 2 weeks in 28-daycycles

Study Arms
Experimental 1
FdCyd (100 mg/m2) + THU (350 mg/m2) administered 5 days/week for 2 weeks in 28-daycycles
Drug : 5-Fluoro-2-Deoxycytidine (FdCyd)
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 THU, an inhibitor of cytidine/deoxycytidine deaminase, has been shown to increase the AUC of the pare 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 DNM and in turn DNA methylation,can result in the re-expression of tumor suppressor genes.

Experimental 1
FdCyd (100 mg/m2) + THU (350 mg/m2) administered 5 days/week for 2 weeks in 28-daycycles
Drug : Tetrahydrouridine (THU)

Arm Intervention/Treatment
Experimental 1
FdCyd (100 mg/m2) + THU (350 mg/m2) administered 5 days/week for 2 weeks in 28-daycycles
Drug : 5-Fluoro-2-Deoxycytidine (FdCyd)
Experimental 1
FdCyd (100 mg/m2) + THU (350 mg/m2) administered 5 days/week for 2 weeks in 28-daycycles
Drug : Tetrahydrouridine (THU)

Recruitment Information

Recruitment Status:Recruiting
Enrollment165
Completion DateJune 02, 2020
Eligibility Criteria: - INCLUSION CRITERIA:
- Patients must have histologically documented metastatic or unresectable non-small cell lung cancer, head and neck cancer, urothelial transitional cell carcinoma, or breast cancer whose disease has progressed after at least one line of standard therapy.
- Patients with solid tumors (non-small cell lung cancer, head and neck cancer, urothelial transitional cell carcinoma, and breast cancer) must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal 10 mm with spiral CT scan. Patients with the above tumor types whose disease is limited to the skin are eligible at the discretion of the PI and must have a physical exam with documentation of skin lesion(s) by color photography, including a ruler to estimate the size of the lesion(s).
- Diagnosis of malignancy must be confirmed by the department of pathology at the institution where the patient is enrolled prior to patient enrollment.
- Any prior therapy must have been completed greater than or equal to 4 weeks prior to enrollment on protocol and the participant must have recovered to eligibility levels from prior toxicity. Patients should be at least six weeks out from nitrosoureas and mitomycin C. Prior radiation should have been completed greater than or equal to 4 weeks prior to study enrollment and all associated toxicities resolved to eligibility levels. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an "early Phase I study" or "pre-Phase I study" where a sub-therapeutic dose of drug is administered) at the PI's discretion, and should have recovered to eligibility levels from any toxicities.
- Age greater than or equal to 18 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 1.5 times institutional upper limit of normal
- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal
- creatinine less than 1.5 times institutional upper limit of normal
OR
--creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels above 1.5 times institutional upper limit of normal.
- Because FdCyd has been shown to be teratogenic in animals, pregnant women will be 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 child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation, and for 3 months after completion of study. 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.
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 or confirmed diagnosis of HIV infection, active infection with Hepatitis B or 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.
-History of allergic reactions attributed to fluoropyrimidines (e.g., capecitabine, fluorouracil, fluorodeoxyuridine) or tetrahydrouridine.
GenderAll
Age18 Years to 120 Years
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
United States

Administrative Information

NCT Number:NCT00978250
Other Study ID Numbers
090214
09-C-0214
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
National Cancer Institute (NCI)
Collaborators
Not Available
Investigators
Principal Investigator
James H Doroshow, M.D.
National Cancer Institute (NCI)