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

Brain and Central Nervous System Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00521183
• Other study ID #: 20057104
• Secondary ID: SCCC-2005097WIRB
• Status: Completed
• Phase: Phase 1
• First received: August 24, 2007
• Last updated: November 24, 2014
• Start date: June 2007
• Est. completion date: May 2014

Study information

• Verified date: November 2014
• Source: University of Miami
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

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.
• 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.

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.

Locations

Country	Name	City	State
United States	University of Miami	Miami	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Brian Lally

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To establish a dose range of CldC for further clinical studies (Phase II clinical trials) based on safety and toxicity.		2 Years	No
Primary	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.		Duration of study treatment	Yes
Secondary	a) Determine the effectiveness of H4U to inhibit systemic cytidine deaminase (CD) during the course of treatment with CldC + H4U.	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	At protocol specified timepoints during treatment	No
Secondary	Cytochlor and metabolite levels in serum at weeks 1, 2, and 3		Pharmacokinetic sampling at protocol-specified timepoints during duration of treatment	No
Secondary	Cytochlor and metabolite levels in urine at weeks 1, 2, and 3		Pharmacokinetic sampling at protocol-specified timepoints during duration of treatment	No