Imaging Study for FdCyd and THU Cancer Treatment

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Background:

- The drugs FdCyd (also called 5-fluoro-2'-deoxcytidine) 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.

Condition or disease	Intervention/treatment	Phase
Head and Neck Neoplasms; Lung Neoplasms; Urinary Bladder Neoplasms; Breast Neoplasms	Drug: [F-18]-5-FLUORO-2'-DEOXYCYTIDINE; Drug: Tetrahydrouridine (IV); Drug: Tetrahydrouridine (oral); Diagnostic Test: PET/CT	Early Phase 1

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 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, NCI, Clinical Center, 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 PET/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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	5 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Diagnostic
Official Title:	Phase 0 Trial of [F-18]-5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine
Study Start Date :	November 1, 2011
Actual Primary Completion Date :	August 4, 2017
Actual Study Completion Date :	August 4, 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1/IV THU; [F-18]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine	Drug: [F-18]-5-FLUORO-2'-DEOXYCYTIDINE; 18FdCyd radiotracer Drug: Tetrahydrouridine (IV); Total dose of THU = 350 mg/m2, IV Drug: Tetrahydrouridine (oral); Total dose of THU is 3000 mg, oral Diagnostic Test: PET/CT; One prior CT and 3 sequential whole body PET
Experimental: 2/Oral THU; [F-18]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine	Drug: [F-18]-5-FLUORO-2'-DEOXYCYTIDINE; 18FdCyd radiotracer Drug: Tetrahydrouridine (IV); Total dose of THU = 350 mg/m2, IV Drug: Tetrahydrouridine (oral); Total dose of THU is 3000 mg, oral Diagnostic Test: PET/CT; One prior CT and 3 sequential whole body PET

Outcome Measures

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Primary Outcome Measures :

1. Safety of [F-18]-5-fluoro-2'-deoxycytidine (FdCyd) administered intravenously with administration of tetrahydrouridine (THU) [ Time Frame: Within 5 days after interventions ]
   List of adverse event frequency
2. Estimate the radiation dosimetry of [F-18]-FdCyd in humans [ Time Frame: 1 year ]
   Radiation dosimetry

Secondary Outcome Measures :

1. To evaluate the pharmacokinetics of [F-18]- FdCyd via PET/CT [ Time Frame: Completion of study ]
   Drug level in the blood
2. To evaluate the distribution of FdCyd in tumorous and nontumoroustissue [ Time Frame: Completion of study ]
   Distribution of FdCyd in tumorous and non-tumorous tissue

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 99 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA:
• Enrolled in the NIH Phase II Clinical protocol evaluating FdCyd with THU (09-C-0214) with target lesion measured as greater than or equal to 10mm with spiral CT scan.
• Written, voluntary, informed consent of the patient must be obtained in compliance with institutional, state and federal guidelines
• For females: Negative serum pregnancy test OR post-menopausal for at least 2 years OR patient has had a hysterectomy

EXCLUSION CRITERIA:

• Participants with severe claustrophobia unresponsive to oral anxiolytics
• Subjects weighing > 400 lbs (weight limit for scanner table), or unable to fit within the imaging gantry
• Known allergy to FdCyd
• The subject is unable to lie still for 75 minutes
• 5 Pregnant or lactating women. Pregnant women are excluded from this study because the effects of 18F-FdCyd in pregnancy are not known. Because there is an unknown but potential risk for adverse events in nursing infants secondary to administration of 18FFdCyd in the mother, breastfeeding should be discontinued if the mother receives 18FFdCyd
• Participants with any co-existing medical or psychiatric condition that is likely to interfere with study procedures and/or results

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Karen A Kurdziel, M.D.	National Cancer Institute (NCI)

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Carter SK. Editorial: Large-bowel cancer-The current status of treatment. J Natl Cancer Inst. 1976 Jan;56(1):3-10.

Doroshow JH, Multhauf P, Leong L, Margolin K, Litchfield T, Akman S, Carr B, Bertrand M, Goldberg D, Blayney D, et al. Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol. 1990 Mar;8(3):491-501.

HARTMANN JR, ORIGENES ML Jr, MURPHY ML, SITARZ A, ERLANDSON M. EFFECTS OF 2'-DEOXY-5-FLUOROURIDINE (NSC-27640) AND 5-FLUOROURACIL (NSC-19893) ON CHILDHOOD LEUKEMIA. Cancer Chemother Rep. 1964 Jan;34:51-4.

ClinicalTrials.gov Identifier:	NCT01479348 History of Changes
Other Study ID Numbers:	120014; 12-C-0014
First Posted:	November 24, 2011
Last Update Posted:	February 27, 2018
Last Verified:	February 13, 2018

Keywords provided by National Institutes of Health Clinical Center (CC):

Imaging; Radiopharmaceutical; Safety	Dosimetry; Drug Distribution; Cancer

Additional relevant MeSH terms:

Neoplasms; Breast Neoplasms; Lung Neoplasms; Head and Neck Neoplasms; Urinary Bladder Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms	Lung Diseases; Respiratory Tract Diseases; Urologic Neoplasms; Urogenital Neoplasms; Urinary Bladder Diseases; Urologic Diseases; Tetrahydrouridine; Antimetabolites; Molecular Mechanisms of Pharmacological Action