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

Study Overview
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Brief Summary
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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 stopping them from dividing. O6-benzylguanine may help carmustine work better by making cancer cells more sensitive to the drug. Giving O6-benzylguanine with carmustine may kill more cancer cells.

Detailed Description
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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: I. To determine the laboratory correlates of clinical response and drug efficacy based upon O6-alkylguanine deoxyribonucleic acid (DNA) alkyltransferase (AGT) activity in CTCL lesions will be examined to determine the effects of consecutive day O6BG administration on the extent and duration of AGT depletion. II. To determine the laboratory correlates of clinical response and drug efficacy based upon degree of induction of apoptosis and cell cycle arrest will be examined in the malignant T-cell population of lymphomatous tissue and in the constitutive cells of the skin to determine drug efficacy and toxicity through immunohistochemical techniques. III. To determine the laboratory correlates of clinical response and drug efficacy based upon O-6-methylguanine-DNA methyltransferase (MGMT) gene mutations and changes in AGT expression will be examined as potential mechanisms for O6BG resistance in non-responding patients. OUTLINE: This is a phase I, dose-escalation study of carmustine followed by a phase II study. Patients receive O6-benzylguanine intravenously (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. After completion of study treatment, patients are followed up at 2 weeks.

Official Title
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A Phase I/II Multicenter Clinical Trial of O6Benzylguanine and Topical Carmustine in the Treatment of Refractory Early-Stage (IA-IIA) Cutaneous T-Cell Lymphoma

Conditions
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Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma, Stage I Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage II Mycosis Fungoides and Sezary Syndrome AJCC v7

Intervention / Treatment
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* Drug: Carmustine
* Other: Laboratory Biomarker Analysis
* Drug: O6-Benzylguanine


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (O6-benzylguanine, carmustine)<br>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. | Drug: Carmustine<br>* Applied topically<br>* Other names: WR-139021;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: O6-Benzylguanine<br>* Given IV<br>* Other names: O(6)-Benzylguanine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | 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. CCR: No evidence of disease, 100% improvement for a duration of at least 4 weeks. PR: Greater than or equal to 50% decrease in SWAT score compared to baseline and improvement is maintained for at least 4 weeks. SD: Less than 50% decrease in SWAT score compared to baseline. PD: Increase of greater or equal to 25% of the SWAT score compared to baseline while the patient is actively taking the study drug | Up to 2 weeks after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity | 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. | Baseline | 
| Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity | 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. | 24 hours after the first infusion | 
| Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity | 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. | 48 hours after the first infusion | 
| Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity | 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. | 1 week after the first infusion | 
| Changes in the Apoptosis | Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 24 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. | at 24 hours after the first infusion | 
| Changes in the Apoptosis | 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. | at 48 hours after the first infusion | 
| Changes in the Cell Cycle/Proliferation | Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 24 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. | at 24 hours after the first infusion | 
| Changes in the Cell Cycle/Proliferation | 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. | at 48 hours after the first infusion | 
| Changes in DNA Damage- Cytotoxicity | 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 | 24 hours after the first infusion | 
| Changes in DNA Damage- Cytotoxicity | 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 | 48 hours after the first infusion | 
| Changes in AGT Inactivation in Non-responding Patients | Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment. | After first course at 2 weeks | 
| Changes in AGT Inactivation in Non-responding Patients | Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment. | After seventh course at 14 weeks |