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

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.

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