Imaging Study for FdCyd and THU Cancer Treatment

Phase 0 Trial of [F-18]-5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine

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....

Study Overview

• Status: Terminated
• Conditions: Breast Neoplasms; Head and Neck Neoplasms; Lung Neoplasms; Urinary Bladder Neoplasms
• Intervention / Treatment: Drug: [F-18]-5-FLUORO-2'-DEOXYCYTIDINE; Drug: Tetrahydrouridine intravenous (IV); Drug: Tetrahydrouridine (oral); Diagnostic test: Positron emission tomography (PET)/Computed tomography (CT)

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Early Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:
• Enrolled in the National Institutes of Health (NIH) Phase II Clinical protocol evaluating 5-fluro-2'-deoxycytidine (FdCyd) with Tetrahydrouridine (THU) (09-C-0214) with target lesion measured as greater than or equal to 10mm with spiral computed tomography (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 18F-FdCyd in the mother, breastfeeding should be discontinued if the mother receives 18F-FdCyd
• Participants with any co-existing medical or psychiatric condition that is likely to interfere with study procedures and/or results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/Intravenous (IV) Tetrahydrouridine (THU); [F-18]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine	Drug: [F-18]-5-FLUORO-2'-DEOXYCYTIDINE; 18FdCyd radiotracer; Other Names: 18FdCyd; Drug: Tetrahydrouridine intravenous (IV); Total dose of THU = 350 mg/m^2, IV; Other Names: THU; Drug: Tetrahydrouridine (oral); Total dose of THU is 3000 mg, oral; Other Names: THU; Diagnostic test: Positron emission tomography (PET)/Computed tomography (CT); One prior CT and 3 sequential whole body PET; Other Names: PET scan/CT scan
Experimental: 2/Oral Tetrahydrouridine (THU); [F-18]-5-fluoro-2'-deoxycytidine plus Tetrahydrouridine	Drug: [F-18]-5-FLUORO-2'-DEOXYCYTIDINE; 18FdCyd radiotracer; Other Names: 18FdCyd; Drug: Tetrahydrouridine intravenous (IV); Total dose of THU = 350 mg/m^2, IV; Other Names: THU; Drug: Tetrahydrouridine (oral); Total dose of THU is 3000 mg, oral; Other Names: THU; Diagnostic test: Positron emission tomography (PET)/Computed tomography (CT); One prior CT and 3 sequential whole body PET; Other Names: PET scan/CT scan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and Severity of Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0	[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.	Within 5 days after interventions
Radiation Dosimetry Estimates of 5-fluoro-2'-Deoxycytidine (FdCyd) in Humans	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.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor to Background Ratios (TBRs) of Target Lesions at 4 Time Points After Injection	Participants were scanned by positron emission tomography (PET) and lesions were measured at 4 time points after injection.	9 minutes, 32 minutes, 56 minutes and 2 hours after injection
Number of Participants With Serious and Non-Serious Adverse Events	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.	Date treatment consent signed to date off study, approximately 20 months and 12 days.

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Carter SK. Editorial: Large-bowel cancer-The current status of treatment. J Natl Cancer Inst. 1976 Jan;56(1):3-10. doi: 10.1093/jnci/56.1.3. No abstract available.
• 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. doi: 10.1200/JCO.1990.8.3.491.
• 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. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2011
• Primary Completion (Actual): August 4, 2017
• Study Completion (Actual): January 11, 2019

Study Registration Dates

• First Submitted: November 22, 2011
• First Submitted That Met QC Criteria: November 22, 2011
• First Posted (Estimate): November 24, 2011

Study Record Updates

• Last Update Posted (Actual): June 2, 2020
• Last Update Submitted That Met QC Criteria: May 21, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Safety; Cancer; Imaging; Dosimetry; Radiopharmaceutical; Drug Distribution
• Additional Relevant MeSH Terms: Skin Diseases; Respiratory Tract Diseases; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Breast Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms; Breast Neoplasms; Head and Neck Neoplasms; Lung Neoplasms; Urinary Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Tetrahydrouridine
• Other Study ID Numbers: 120014; 12-C-0014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No