Imaging Study for FdCyd and THU Cancer Treatment

Early Phase 1

Terminated

Conditions: Head and Neck Neoplasms
Lung Neoplasms
Urinary Bladder Neoplasms
Breast Neoplasms

Interventions: Drug: [F-18]-5-FLUORO-2'-DEOXYCYTIDINE
Drug: Tetrahydrouridine intravenous (IV)
Drug: Tetrahydrouridine (oral)
Diagnostic Test: Positron emission tomography (PET)/Computed tomography (CT)

Registration Number: NCT01479348

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

- The drugs FdCyd (also called 5-fluoro-2'-deoxycytidine) and THU (also called tetrahydrouridine) are being used in a cancer treatment study. Not a lot is known about how FdCyd works in the body. Researchers want to look at a modified form of FdCyd using imaging studies to see how the drug reacts with the cancer. This study is not a treatment study. It is open only to people who are already on the FdCyd and THU cancer treatment study.

Objectives:

- To study how FdCyd affects advanced cancer cells.

Eligibility:

- Participants in National Cancer Institute study 09-C-0214.

Design:

* Participants will have two imaging studies, one before starting FdCyd and THU treatment and one after starting treatment.

* Participants will have the modified FdCyd, known as F-18 FdCyd, with a dose of THU. The doses will be followed by two imaging study scans and frequent blood samples.

* This procedure will be repeated at a later date, during the FdCyd and THU treatment period.

* Treatment will not be provided as part of this study. This is an imaging study protocol only....

Detailed Description: BACKGROUND:

- In pre-clinical models, 5-fluoro-2-deoxycytidine (FdCyd), administered along with

tetrahydrouridine (THU; an inhibitor of cytidine/deoxycytidine deaminase), has shown superior anti-tumor activity as compared with 5-fluorouracil.

- FdCyd can be phosphorylated to 5-fluoro-2-deoxycytidylate (FdCMP) by deoxycytidine

kinase and the nucleotide deaminated to FdUMP by deoxycytidylate (dCMP) deaminase.

The activity of dCMP deaminase is reported to be higher in human malignancies than in normal tissues, which may result in selective cytotoxicity.

* FdCyd is an inhibitor of deoxyribonucleic acid (DNA) methyltransferase and DNA methylation, resulting in reexpression of genes silenced by DNA hypermethylation. It is being evaluated in a phase II multihistology clinical trial at the Developmental Therapeutics Clinic, National Cancer Institute (NCI), Clinical Center, National Institutes of Health (NIH).

* While FdCyd + THU has shown preliminary evidence of activity in early phase trials not all patients show clinical response. The establishment of a radiolabeled form to image the biodistribution in vivo at baseline and during therapy may provide insight into the distribution of the therapeutic drug.

* The first step in the development of such an in vivo marker is to determine the

biodistribution and safety of the radiolabeled form.

OBJECTIVES:

* Determine the safety of \[F-18\]-5-fluoro-2'-deoxycytidine (FdCyd) administered intravenously with administration of tetrahydrouridine (THU).

* Estimate the radiation dosimetry of \[F-18\]-FdCyd in humans.

ELIGIBILITY:

* Only patients enrolled in NCI Phase II Study evaluating FdCyd with THU (NCI Protocol # 09-C-0214 (CTEP# 8351) or NCI Protocol #12-C-0066 (CTEP# 9127)) at the NIH Clinical Center will be eligible to participate in this study).

* Patients must have a target lesion greater than or equal to 10mm

* May not be pregnant or lactating; must be less than or equal to 350 lbs; and may not have known allergy to FdCyd or contraindications to positron emission tomography (PET)/computed tomography (CT) imaging.

DESIGN:

* There are two arms to this study

* The first arm will be patients enrolling in the therapeutic Phase II 5-FdCyd/THU study (NCI Protocol # 09-C-0214 (CTEP# 8351) in the NCI Developmental Therapeutics Clinic

* The second arm will be patients enrolling in the Phase I 5-FdCyd/THU study (NCI Protocol #12-C-0066 (CTEP# 9127)) in the NCI Developmental Therapeutics Clinic.

* Patients will undergo an initial \[F-18\]-FdCyd + THU PET/CT imaging prior to therapeutic dosing on study NCI Protocol # 09-C-0214 (CTEP# 8351) or NCI Protocol #12-C-0066 (CTEP# 9127). Repeat imaging will be performed while the patient is receiving FdCyd + THU therapy under the parent therapeutic protocol. This imaging must be completed 2-5 days after cycle start and at least 2 hours after a dose. Upon completion of repeat imaging, patients will be taken off this imaging study 24 hours after the last imaging session.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1/Intravenous (IV) Tetrahydrouridine (THU)	[F-18]-5-FLUORO-2'-DEOXYCYTIDINE	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine
1/Intravenous (IV) Tetrahydrouridine (THU)	Tetrahydrouridine (oral)	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine
1/Intravenous (IV) Tetrahydrouridine (THU)	Positron emission tomography (PET)/Computed tomography (CT)	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine
2/Oral Tetrahydrouridine (THU)	[F-18]-5-FLUORO-2'-DEOXYCYTIDINE	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine
2/Oral Tetrahydrouridine (THU)	Tetrahydrouridine (oral)	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine
2/Oral Tetrahydrouridine (THU)	Positron emission tomography (PET)/Computed tomography (CT)	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine
1/Intravenous (IV) Tetrahydrouridine (THU)	Tetrahydrouridine intravenous (IV)	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine
2/Oral Tetrahydrouridine (THU)	Tetrahydrouridine intravenous (IV)	\[F-18\]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine

Primary Outcome Measures

Name	Time	Method
Frequency and Severity of Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0	Within 5 days after interventions	\[F-18\]-5-fluoro-2'-deoxycytidine (FdCyd) was administered intravenously with administration of tetrahydrouridine (THU) and the frequency and severity of adverse events was observed. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 0 is normal, Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe or medically significant but not immediately life-threatening, Grade 4 is life-threatening consequences, and Grade 5 is death related to adverse event.
Radiation Dosimetry Estimates of 5-fluoro-2'-Deoxycytidine (FdCyd) in Humans	1 year	Radiation dosimetry was determined based on the first patients. This involved making region of interest measurements on the scan for each major organ and measuring the uptake. Using standard dosimetry software this is converted into mSv/MBq, a standard measure of dosimetry. The software is known as Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA) and is commonly used to generate this kind of data.

Secondary Outcome Measures

Name	Time	Method
Tumor to Background Ratios (TBRs) of Target Lesions at 4 Time Points After Injection	9 minutes, 32 minutes, 56 minutes and 2 hours after injection	Participants were scanned by positron emission tomography (PET) and lesions were measured at 4 time points after injection.
Number of Participants With Serious and Non-Serious Adverse Events	Date treatment consent signed to date off study, approximately 20 months and 12 days.	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.