5-Fluoro-2'-Deoxcyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer

NCT00359606 | Completed Phase 1 DMC

• 5 other identifiers: 98127PHI-16UM1CA62505NCI-2015-0065506-C-0221
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 4

Brief Summary

This phase I trial studies the side effects and best dose of 5-fluoro-2-deoxycytidine when given together with tetrahydrouridine in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Drugs used in chemotherapy, such as 5-fluoro-2-deoxycytidine and tetrahydrouridine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Conditions

Neoplasms

Keywords

DNA Methylation; Advanced Cancer; Methyltransferase Inhibitor; Epigenetics; Gene Re-Expression

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD) of 5-fluoro-2-deoxycytidine (FdCyd) when given with tetrahydrouridine (THU) determined by dose-limiting toxicities

  MTD is defined as the highest dose tested in which \< 33% of patients experienced dose limiting toxicity. The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by National Cancer Institute Common Toxicity Criteria version 2.0 and nadir or maximum values for the laboratory measures), time of onset (i.e., cycle number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by cycle.

  28 days

• Survival

  Survival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.

  Time from registration to time of death due to any cause, assessed up to 13 years

• Time to treatment failure

  Survival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.

  Time from registration to the first observation of disease progression, death due to any cause, or early discontinuation of treatment, assessed up to 13 years

Other Outcomes (2)

• Levels of mRNA's of interest

  Up to 13 years

• Pharmacokinetic parameters of 5-fluoro-2-deoxycytidine in combination with tetrahydrouridine

  Baseline, 15 & 30 minutes, 1, 2, 4, 6, 9 hours on days 1 & 8; baseline, 15 & 30 minutes, 1, 2, 2.5 hours after infusion start & 15 & 30 minutes, 1, 2, 4, 6 hours after infusion end on day 2; baseline on days 3, 9, & 15; 2.5 hours after infusion on day 12

Study Arms (1)

Treatment (5-fluoro-2-deoxycytidine, tetrahydrouridine)

EXPERIMENTAL

Patients receive tetrahydrouridine PO on day 1; 5-fluoro-2-deoxycytidine PO on days 1 and 8; tetrahydrouridine IV over 3 hours on days 2-5, 8, and 9-12; and 5-fluoro-2-deoxycytidine IV over 3 hours on days 2-5 and 9-12 of course 1. For all subsequent courses, patients receive tetrahydrouridine IV over 3 hours and 5-fluoro-2-deoxycytidine IV over 3 hours on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: 5-Fluoro-2-Deoxycytidine (FdCyd); Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Tetrahydrouridine (THU)

Interventions

5-Fluoro-2-Deoxycytidine (FdCyd) DRUG

Given PO and IV

Also known as: 5-FLUORO-2'-DEOXYCYTIDINE, 5-fluoro-2-deoxycytidine, FdCyd, Ro 5-1090

Treatment (5-fluoro-2-deoxycytidine, tetrahydrouridine)

Laboratory Biomarker Analysis OTHER

Correlative Studies

Treatment (5-fluoro-2-deoxycytidine, tetrahydrouridine)

Pharmacological Study OTHER

Correlative Studies

Treatment (5-fluoro-2-deoxycytidine, tetrahydrouridine)

Tetrahydrouridine (THU) DRUG

Given PO and IV

Also known as: Tetrahydrouridine, THU

Treatment (5-fluoro-2-deoxycytidine, tetrahydrouridine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Advanced, histologically-confirmed neoplastic disease refractory to standard therapy or for which no standard therapy exists
• Karnofsky performance status of at least 60% and estimated survival of at least two months
• Serum creatinine =\< 2.0 mg/dl or creatinine clearance \>= 50 ml/min
• Absolute neutrophil count (ANC) \>= 1,500/ul
• Platelets \>= 125,000/ul
• Bilirubin =\< 1.5 mg/dl
• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =\< 3 times the upper limits of normal
• Prior antineoplastic therapy must have been completed at least four weeks prior to the patient's entry on this study, or patients must have recovered from any expected side effects of the prior therapy; there is no limit on the number of cycles of prior chemotherapy
• Patients must be ineligible for or have refused participation in higher priority institutional protocols
• Written, voluntary, informed consent of the patient must be obtained in compliance with institutional, state and federal guidelines
• Pregnant patients are INELIGIBLE; all patients of child-bearing potential, both male and female, must be advised to practice adequate contraception; premenopausal women must have a negative pregnancy test prior to entry on this study
• Patients with any non-malignant intercurrent illness (e.g. cardiovascular, pulmonary, or central nervous system disease) which is either poorly controlled with currently available treatment, or which is of such severity that the investigators deem it inappropriate to treat the patient on this protocol are INELIGIBLE
• Patients currently being treated for a severe infection or who are recovering from major surgery are INELIGIBLE until recovery is deemed complete by the investigators
• The presence of measurable disease is NOT required for this phase I study; if bidimensionally measurable disease is present, baseline measurements of up to 3 indicator lesions should be made no earlier than four weeks prior to the first cycle of chemotherapy; pleural effusions, ascites and bone metastases are not considered measurable
• Complete blood count (CBC), differential count, platelet count, and blood chemistries should be done no earlier than 72 hours prior to each cycle of chemotherapy

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (4)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90089, United States

Location

University of California, Davis Cancer Center

Sacramento, California, 95817, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 1255749 BACKGROUND

• 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.

  PMID: 2407810 BACKGROUND

• Keyomarsi K, Moran RG. Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res. 1986 Oct;46(10):5229-35.

  PMID: 2944577 BACKGROUND

• Holleran JL, Beumer JH, McCormick DL, Johnson WD, Newman EM, Doroshow JH, Kummar S, Covey JM, Davis M, Eiseman JL. Oral and intravenous pharmacokinetics of 5-fluoro-2'-deoxycytidine and THU in cynomolgus monkeys and humans. Cancer Chemother Pharmacol. 2015 Oct;76(4):803-11. doi: 10.1007/s00280-015-2857-x. Epub 2015 Sep 1.

  PMID: 26321472 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms

Interventions

5-fluoro-2'-deoxycytidine; Tetrahydrouridine

Intervention Hierarchy (Ancestors)

Uridine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Robert Morgan, MD

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 1, 2006
• First Posted: August 2, 2006
• Study Start: April 1, 1999
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: May 6, 2015

Record last verified: 2015-05

Locations

US (4)