Cytochlor, Tetrahydrouridine, and External-Beam Radiation Therapy in Treating Patients With Cancer That Has Spread to the Brain - Full Text View

Purpose

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as cytochlor and tetrahydrouridine, may make tumor cells more sensitive to radiation therapy.

PURPOSE: This phase I trial is studying the side effects and best dose of cytochlor when given together with tetrahydrouridine and external-beam radiation therapy in treating patients with cancer that has spread to the brain.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Drug: Cytochlor Drug: Tetrahydrouridine Radiation: Radiation Therapy	Phase 1

Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Translational Phase I Trial of Escalating Doses of 5-Chloro-2'-Deoxycytidine (CldC) With a Fixed Dose of Tetrahydrouridine Combined With External Brain Radiation for Metastatic Carcinoma to the Brain

Resource links provided by NLM:

MedlinePlus related topics: Cancer

U.S. FDA Resources

Further study details as provided by University of Miami Sylvester Comprehensive Cancer Center:

Primary Outcome Measures:

To establish a dose range of CldC for further clinical studies (Phase II clinical trials) based on safety and toxicity. [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
b) Establish the safety and toxicity profile of CldC+ H4U when given in combination with RT for 2 weeks following treatment with the drug alone for 3 days in the week prior to the combined treatment. [ Time Frame: Duration of study treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

a) Determine the effectiveness of H4U to inhibit systemic cytidine deaminase (CD) during the course of treatment with CldC + H4U. [ Time Frame: At protocol specified timepoints during treatment ] [ Designated as safety issue: No ]
Baseline Levels of CD will be obtained by assaying CD in serum prior to initiation of treatment on Wednesday of week 1. Follow-up assays of CD in serum will be made on the Fridays of weeks 1 to 3 after each day's treatment with CldC + H4U. In weeks 2 and 3 this will take place prior to RT
Cytochlor and metabolite levels in serum at weeks 1, 2, and 3 [ Time Frame: Pharmacokinetic sampling at protocol-specified timepoints during duration of treatment ] [ Designated as safety issue: No ]
Cytochlor and metabolite levels in urine at weeks 1, 2, and 3 [ Time Frame: Pharmacokinetic sampling at protocol-specified timepoints during duration of treatment ] [ Designated as safety issue: No ]

Estimated Enrollment:	18
Study Start Date:	June 2007
Estimated Primary Completion Date:	September 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: CldC + H4U	Drug: Cytochlor The study's starting dose of CldC is 50 mg/m2/day. The dose of CldC will be escalated / de-escalated for patients. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3. Other Name: CldC, CDC Drug: Tetrahydrouridine A fixed dose of H4U at 720 mg/m2/day will be used, regardless of the dose of CldC administered. H4U will be delivered by an IV bolus infusion over a period of 5 minutes, followed 5 minutes later by an IV bolus infusion of CldC. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3. Other Name: THU, H4U Radiation: Radiation Therapy One treatment of 3 Gy will be given daily 5 days per week (10 fractions) for a total of 30 Gy over two weeks.

Arms

Assigned Interventions

Experimental: CldC + H4U

Drug: Cytochlor

The study's starting dose of CldC is 50 mg/m2/day. The dose of CldC will be escalated / de-escalated for patients. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3.

Other Name: CldC, CDC

Drug: Tetrahydrouridine

A fixed dose of H4U at 720 mg/m2/day will be used, regardless of the dose of CldC administered. H4U will be delivered by an IV bolus infusion over a period of 5 minutes, followed 5 minutes later by an IV bolus infusion of CldC. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3.

Other Name: THU, H4U

Radiation: Radiation Therapy

One treatment of 3 Gy will be given daily 5 days per week (10 fractions) for a total of 30 Gy over two weeks.

Detailed Description:

OBJECTIVES:

Primary

Establish the safety and toxicity profile of cytochlor and H4U when given in combination with external-beam radiotherapy for 2 weeks after treatment with the drugs alone in the previous week.

Secondary

Determine the effectiveness of H4U to inhibit systemic cytidine deaminase (CD) during the course of treatment with cytochlor and H4U.
Perform detailed pharmacokinetic studies to determine the levels of cytochlor and its metabolites in serum and in urine in weeks 1, 2, and 3 during treatment.

OUTLINE: This is a dose-escalation study of cytochlor.

Patients receive cytochlor IV and tetrahydrouridine (H4U) IV over 5 minutes on 3 days in week 1 and on days 1-5 in weeks 2 and 3. Patients also undergo external-beam radiotherapy 5 days a week in weeks 2 and 3 initiated 3-4 hours after infusions of cytochlor and H4U. Treatment may repeat in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed monthly for 3 months, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then yearly thereafter.

Eligibility

Ages Eligible for Study:	21 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosis of metastatic cancer to the brain by contrast-enhanced MRI or CT scan
Eligible for whole-brain radiotherapy (WBRT)
- Patients treated with prior surgery are eligible if WBRT is to be used post operatively
- Not planning to be treated with stereotactic radiosurgery
No leptomeningeal metastasis documented by contrast-enhanced MRI/CT scan or cerebrospinal fluid evaluation

PATIENT CHARACTERISTICS:

Inclusion criteria:

Karnofsky performance status (PS) 70-100% or ECOG PS 0-1
Leukocytes ≥ 3,000/µL
Absolute neutrophil count > 1,500/µL
Platelet count > 100,000/µL
Total bilirubin normal
AST and ALT < 2.5 times upper limit of normal
Creatinine normal OR creatinine clearance > 60 mL/min
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation

Exclusion criteria:

Uncontrolled intercurrent illness including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness/social situations that would limit compliance with study requirements
Pregnant or lactating
Alcohol dependence

PRIOR CONCURRENT THERAPY:

No prior radiotherapy to the brain
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent chemotherapy, immunotherapy, hormonal therapy (excluding contraceptives and replacement steroids), or other experimental medication
No other concurrent anticancer therapy outside the protocol
- Systemic therapy one month before or after brain radiotherapy is allowed
No concurrent heparin or coumadin

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00521183

Locations

United States, Florida
University of Miami Sylvester Comprehensive Cancer Center - Miami	Recruiting
Miami, Florida, United States, 33136
Contact: University of Miami Sylvester Comprehensive Cancer Center Clin 866-574-5124 Sylvester@emergingmed.com

Sponsors and Collaborators

University of Miami Sylvester Comprehensive Cancer Center

Investigators

Study Chair:

Brian Lally, MD

University of Miami Sylvester Comprehensive Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT00521183 History of Changes
Other Study ID Numbers:	EPROST-20057104, SCCC-2005097, WIRB-20051340
Study First Received:	August 24, 2007
Last Updated:	April 18, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Miami Sylvester Comprehensive Cancer Center:

adult tumors metastatic to brain

Additional relevant MeSH terms:

Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Nervous System Diseases

Tetrahydrouridine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 16, 2013