Benzoylphenylurea in Treating Patients With Advanced Solid Tumors

Phase I Study of Continuous Weekly Dosing of Dimethyl Benzoylphenylurea (BPU) in Patients With Solid Tumors Not Responding to Conventional Therapy

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase I trial to study the effectiveness of benzoylphenylurea in treating patients who have advanced solid tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: benzoylphenylurea

Detailed Description

OBJECTIVES:

• Determine the maximum tolerated dose of benzoylphenylurea in patients with advanced solid tumors.
• Evaluate the acute and chronic toxicity profile of this regimen in these patients.
• Evaluate the pharmacokinetics and metabolites of this regimen and any potential correlation with pharmacodynamic effects in these patients.
• Determine the antitumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive oral benzoylphenylurea (BPU) once weekly. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of BPU until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience a dose-limiting toxicity. Once the MTD is determined, 12 additional patients are accrued and treated with BPU as above to confirm the MTD.

Patients are followed for 30 days.

PROJECTED ACCRUAL: Approximately 18-24 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

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

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed malignancy

  • Metastatic or unresectable
  • No effective standard curative or palliative measures exist
• No known CNS or brain metastasis

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin normal
• SGOT/SGPT normal

Renal:

• Creatinine normal
• Creatinine clearance at least 60 mL/min

Cardiovascular:

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No uncontrolled ventricular arrhythmia
• No myocardial infarction within the past 3 months
• No superior vena cava syndrome

Neurologic:

• No grade 1 or greater peripheral neuropathy
• No uncontrolled major seizure disorder
• No spinal cord compression

Other:

• No active serious infection requiring IV antibiotics
• No concurrent uncontrolled illness
• No concurrent unstable or serious medical condition
• No chronic diarrhea or malabsorption
• No history of allergic reactions to compounds similar in chemical or biological composition to benzoylphenylurea
• No psychiatric illness or social situation that would preclude study compliance
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent immunotherapy
• No concurrent growth factors during first 2 courses of study
• Concurrent epoetin alfa allowed

Chemotherapy:

• At least 28 days since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No other concurrent chemotherapy

Endocrine therapy:

• No concurrent hormonal therapy

Radiotherapy:

• At least 28 days since prior large-field radiotherapy
• Prior palliative radiotherapy for painful bone metastases allowed
• No concurrent radiotherapy, including palliative or whole-brain radiotherapy for CNS disease

Surgery:

• At least 28 days since prior major surgery

Other:

• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational or commercial agents or therapies for the malignancy
• No other concurrent investigational agents
• Concurrent bisphosphonates allowed if bone metastases are not only site of measurable or evaluable disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: benzoylphenylurea	Drug: benzoylphenylurea

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine Maximum Tolerated Dose of BPU	Toxicity was assessed weekly during the first 2 cycles, and monthly thereafter, using the National Cancer Institute Common Toxicity Criteria (NCI CTCv2). Dose limiting toxicity (DLT) was defined as dose delays >2 weeks, grade 4 haematologic toxicity (except grade 4 neutropenia lasting <5 days), or grade 3 nonhaematologic toxicity. The maximum tolerated dose (MTD) is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience a dose-limiting toxicity.	4 weeks (1 course of treatment for each subject)

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Patients With Adverse Events	every 4 weeks
Area Under the Plasma Concentration Versus Time Curve (AUC) of BPU	8 weeks
Test for Antitumor Activity in Blood and Tissue	baseline

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Antonio C. Wolff, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

General Publications

• Messersmith WA, Rudek MA, Baker SD, Zhao M, Collins C, Colevas AD, Donehower RC, Carducci MA, Wolff AC. Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours. Eur J Cancer. 2007 Jan;43(1):78-86. doi: 10.1016/j.ejca.2006.09.006. Epub 2006 Nov 3.
• Messersmith WA, Baker SD, Donehower RC, et al.: Phase I study of continuous weekly dosing of dimethyl benzoylphenylurea (BPU) in patients with solid tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-815, 2003.

Study record dates

Study Major Dates

• Study Start: March 1, 2001
• Primary Completion (Actual): August 1, 2004
• Study Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: May 6, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): March 25, 2013
• Last Update Submitted That Met QC Criteria: March 18, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: J0072 CDR0000068625; P30CA006973 (U.S. NIH Grant/Contract); U01CA070095 (U.S. NIH Grant/Contract); JHOC-J0072 (Other Identifier: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins); NCI-1351 (Other Grant/Funding Number: National Cancer Institute)