O6-Benzylguanine and Topical Carmustine in Treating Patients With Early-Stage IA-IIA Cutaneous T-Cell Lymphoma

Phase 1

Completed

• Conditions: Stage II Mycosis Fungoides and Sezary Syndrome AJCC v7; Stage I Mycosis Fungoides and Sezary Syndrome AJCC v7; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
• Interventions: Drug: Carmustine; Other: Laboratory Biomarker Analysis; Drug: O6-Benzylguanine

• Registration Number: NCT00961220
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase I/II trial studies the side effects and best dose of carmustine when given together with O6-benzylguanine and to see how well they work in treating patients with stage IA-IIA cutaneous T-cell lymphoma. Drugs used in chemotherapy, such as carmustine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stoppi...

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the cutaneous T-cell Lymphoma (CTCL) response rate and safety of O6BG (O6-benzylguanine) /BCNU (carmustine) when given biweekly as two consecutive daily doses.

SECONDARY OBJECTIVES:
...

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2009-08-16
• Study First Submitted QC: 2009-08-16
• Study First Posted: 2009-08-18
• Study Start: 2010-02-01
• Primary Completion: 2012-04-08
• Study Completion: 2014-04-08
• Results First Submitted: 2015-03-11
• Results First Submitted QC: 2015-03-11
• Results First Posted: 2015-03-23
• Status Verified: 2018-04
• Last Update Submitted: 2018-04-23
• Last Update Posted: 2018-05-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 17

Inclusion Criteria

• Diagnosis of CTCL stages IA-IIA by histopathology and immunohistochemistry in screening biopsies confirmed at Case Western Reserve University within 6 months of enrollment; biopsies may be performed at the site of collaborating institutions and shipped to University Hospitals of Cleveland-Case Western Reserve University (UHC-CWRU)
• Performance status Eastern Cooperative Oncology Group (ECOG) grade 0, 1, or 2
• Patients must have recovered from toxicity of prior treatment and have received no CTCL therapy other than emollition for at least 4 weeks, with the exception of topical corticosteroids, which may be used up to 2 weeks before the trial start date
• Patients must have signed a consent form indicating the investigational nature of the treatment and its potential side effects
• White blood cell (WBC) at least 3.5 x10E9/L
• Absolute neutrophil count (ANC) at least 1.6 x10E9/L
• Platelets > 100,000/ul
• Bilirubin < 1.5 mg/dL
• Serum glutamic oxaloacetic transaminase (SGOT) within normal range
• Creatinine =< 1.5 mg/dL
• Electrolytes normal
• Controlled (diet and insulin) diabetes is permitted
• Demonstration of clinically normal lung function based on history and physical examination; patients with clinical evidence of pulmonary disease as determined by the investigator should have baseline lung function tests performed with demonstration of diffusing capacity of the lung for carbon monoxide (DLCO) >= 70%; a DLCO single breath, adjusted for hemoglobin, will be utilized; we will not use DLCO/alveolar volume (VA) for inclusion or exclusion in this study
• Patients must have cutaneous disease that is amenable to biopsy and must be willing to undergo several sequential biopsies
• Must have failed at least one conventional treatment for CTCL other than topical corticosteroids; this includes phototherapy, topical mechlorethamine, topical or oral bexarotene, radiation therapy, photopheresis, chemotherapy, and immunomodulatory agents such as interferon and other retinoids

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Exclusion Criteria

• Patients who have received prior treatment with topical or systemic BCNU or other nitrosoureas
• Patients with known central nervous system involvement or primary central nervous system (CNS) malignancies
• Patients with performance status ECOG grade 3 or 4
• Pregnant women, women who are breast feeding infants, or women with reproductive potential not practicing adequate contraception
• Patients with an active infection which requires hospitalization, or which may affect the patient?s safety if the patient was enrolled
• Patients with pulmonary disease as determined by history, physical examination, chest X-ray, or pulse oximetry with < 70% predicted DLCO
• CTCL patients with stage IIB-IVB disease

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (O6-benzylguanine, carmustine)	Laboratory Biomarker Analysis	Patients receive O6-benzylguanine IV over 1 hour and apply topical carmustine to the total skin surface (excluding the lips, eyelids, and ulcerated lesions) 1 hour after completing O6-benzylguanine infusion on days 1-2. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Treatment (O6-benzylguanine, carmustine)	Carmustine	Patients receive O6-benzylguanine IV over 1 hour and apply topical carmustine to the total skin surface (excluding the lips, eyelids, and ulcerated lesions) 1 hour after completing O6-benzylguanine infusion on days 1-2. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Treatment (O6-benzylguanine, carmustine)	O6-Benzylguanine	Patients receive O6-benzylguanine IV over 1 hour and apply topical carmustine to the total skin surface (excluding the lips, eyelids, and ulcerated lesions) 1 hour after completing O6-benzylguanine infusion on days 1-2. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate	Up to 2 weeks after completion of study treatment	Based on changes in modified SWAT assessment, patient responses will be classified as complete clinical response (CCR), partial response (PR), stable disease (SD), or progressive disease (PD). SWAT provides an accurate and reproducible assessment of cutaneous disease involvement based on body surface area of involvement and lesional thickness.; ...

Secondary Outcome Measures

Name	Time	Method
Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity	1 week after the first infusion	Examine AGT depletion at baseline, 24 hrs or 48 hrs, and 1 week after the first Infusion of O6BG. AGT levels will be determined by biochemical activity assay.
Changes in the Apoptosis	at 48 hours after the first infusion	Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 48 hours, using immunohistochemical staining for Ki-67, PCNA, bcl-2, and caspase-3, as well as y2HAX and TUNEL assays. The apoptotic index will be calculated from these results.
Changes in the Cell Cycle/Proliferation	at 48 hours after the first infusion	Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 48 hours, using immunohistochemical staining for Ki-67, PCNA, bcl-2, and caspase-3, as well as y2HAX and TUNEL assays. The proliferation rate will be calculated from these results.
Changes in AGT Inactivation in Non-responding Patients	After seventh course at 14 weeks	Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment.
Changes in DNA Damage- Cytotoxicity	48 hours after the first infusion	Immunohistochemistry will be used to assess expression of these proteins in keratinocytes, epidermal lymphocytes, and dermal lymphocytes, to determine the effects of BCNU cytotoxicity in each subpopulation of cells

Trial Locations

Locations (4)

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

Case Comprehensive Cancer Center; 🇺🇸 Cleveland, Ohio, United States

Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States