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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00961220
• Collaborator: (none)
• Enrollment: 17
• Locations: 4
• Arm: 1
• Actual Duration (Months): 50.2
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Carmustine; Other: Laboratory Biomarker Analysis; Drug: O6-Benzylguanine	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. 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.

3. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Apr 8, 2012
• Actual Study Completion Date: Apr 8, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (O6-benzylguanine, 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.

Drug: Carmustine; Applied topically; Other Names: BCNU Becenum Becenun BiCNU Bis(chloroethyl) Nitrosourea Bis-Chloronitrosourea Carmubris Carmustin Carmustinum FDA 0345 Gliadel N,N'-Bis(2-chloroethyl)-N-nitrosourea Nitrourean Nitrumon SK 27702 SRI 1720 WR-139021 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: O6-Benzylguanine; Given IV; Other Names: 6-O-Benzylguanine O(6)-Benzylguanine

Outcome Measures

Primary Outcome Measures

1. 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. 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

Secondary Outcome Measures

1. Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity [Baseline]

   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.

2. Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity [24 hours 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.

3. Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity [48 hours 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.

4. 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.

5. Changes in the Apoptosis [at 24 hours after the first infusion]

   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.

6. 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.

7. Changes in the Cell Cycle/Proliferation [at 24 hours after the first infusion]

   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.

8. 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.

9. Changes in DNA Damage- Cytotoxicity [24 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

10. 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

11. Changes in AGT Inactivation in Non-responding Patients [After first course at 2 weeks]

    Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment.

12. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Henry Ford Hospital	Detroit	Michigan	United States	48202
2	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
3	Case Western Reserve University	Cleveland	Ohio	United States	44106
4	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kevin Cooper, Case Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00961220
• Other Study ID Numbers: NCI-2012-02927; NCI-2012-02927; 3405; CASE 3405-CC304; 7080; P30CA043703; R21CA115057; U01CA062502
• First Posted: Aug 18, 2009
• Last Update Posted: May 22, 2018
• Last Verified: Apr 1, 2018

• Additional relevant MeSH terms: Mycoses; Lymphoma; Lymphoma, T-Cell; Mycosis Fungoides; Sezary Syndrome; Lymphoma, T-Cell, Cutaneous; Syndrome; Carmustine; O(6)-benzylguanine

Study Results

Participant Flow

Recruitment Details	Patients were recruited from February 2010 to November 2013 from University Hospital Case Medical Center.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	17
COMPLETED	10
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Overall Participants	17
Age, Customized (participants) [Number]
20-29 years	2 11.8%
30-39 years	5 29.4%
40-49 years	4 23.5%
50-59 years	2 11.8%
60-69 years	3 17.6%
70-79 years	1 5.9%
Sex: Female, Male (Count of Participants)
Female	5 29.4%
Male	12 70.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	17 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 29.4%
White	12 70.6%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	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
Time Frame	Up to 2 weeks after completion of study treatment

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV carmustine: Applied topically laboratory biomarker analysis: Correlative studies
Measure Participants	17
Complete Clinical Response-confirmed	6 35.3%
Complete Clinical Response-unconfirmed	2 11.8%
Partial Response	8 47.1%
Progressive Disease	1 5.9%

2. Secondary Outcome

Title	Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour carmustine: Applied topically. BCNU will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
Description	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.
Time Frame	24 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour carmustine: Applied topically. BCNU will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
Description	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.
Time Frame	48 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour carmustine: Applied topically. BCNU will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

5. Secondary Outcome

Title	Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
Description	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.
Time Frame	1 week after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour carmustine: Applied topically. BCNU will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

6. Secondary Outcome

Title	Changes in the Apoptosis
Description	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.
Time Frame	at 24 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour carmustine: Applied topically. BCNU will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

7. Secondary Outcome

Title	Changes in the Apoptosis
Description	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.
Time Frame	at 48 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

8. Secondary Outcome

Title	Changes in the Cell Cycle/Proliferation
Description	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.
Time Frame	at 24 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

9. Secondary Outcome

Title	Changes in the Cell Cycle/Proliferation
Description	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.
Time Frame	at 48 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

10. Secondary Outcome

Title	Changes in DNA Damage- Cytotoxicity
Description	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
Time Frame	24 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

11. Secondary Outcome

Title	Changes in DNA Damage- Cytotoxicity
Description	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
Time Frame	48 hours after the first infusion

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

12. Secondary Outcome

Title	Changes in AGT Inactivation in Non-responding Patients
Description	Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment.
Time Frame	After first course at 2 weeks

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour carmustine: Applied topically. BCNU will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

13. Secondary Outcome

Title	Changes in AGT Inactivation in Non-responding Patients
Description	Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment.
Time Frame	After seventh course at 14 weeks

Outcome Measure Data

Analysis Population Description

Attempts to stain AGT and caspase 3 were unsuccessful and there were no remaining tissues for other outcomes.

Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour carmustine: Applied topically. BCNU will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Adverse events were collected from during treatment over a 6 month time period.
Arm/Group Title	Treatment (O6-benzylguanine, Carmustine)
Arm/Group Description	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. O6-benzylguanine: Given IV. 120 mg/m2 over 1 hour Carmustine (BCNU) will begin at a starting dose of 20 mg on Day 1. Beyond this first dose level, for each of the subsequent four patients enrolled, the BCNU dose will be escalated up to a limit of 40 mg total (given on day 1 only). laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (O6-benzylguanine, Carmustine)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (O6-benzylguanine, Carmustine)
	Affected / at Risk (%)	# Events
Total	0/17 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (O6-benzylguanine, Carmustine)
	Affected / at Risk (%)	# Events
Total	16/17 (94.1%)
Blood and lymphatic system disorders
ANEMIA	3/17 (17.6%)
LEUKOPENIA	1/17 (5.9%)
MONOCYTE ELEVATION	1/17 (5.9%)
Gastrointestinal disorders
BLOATING	1/17 (5.9%)
CONSTIPATION	1/17 (5.9%)
NAUSEA	8/17 (47.1%)
General disorders
FATIGUE	10/17 (58.8%)
INJECTION SITE REACTION or PAIN	2/17 (11.8%)
Investigations
ALKALINE PHOSPHATASE ELEVATED	1/17 (5.9%)
CREATININE ELEVATION	1/17 (5.9%)
TOTAL BILIRUBIN ELEVATED	1/17 (5.9%)
TRANSAMINASE ELEVATION	9/17 (52.9%)
Metabolism and nutrition disorders
GLUCOSE LOW	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
JOINT PAINS	1/17 (5.9%)
MYALGIA	1/17 (5.9%)
Nervous system disorders
DIZZINESS	2/17 (11.8%)
HEADACHE	8/17 (47.1%)
Renal and urinary disorders
URIC ACID ELEVATION	2/17 (11.8%)
URINE SPECIFIC GRAVITY ELEVATED	2/17 (11.8%)
Skin and subcutaneous tissue disorders
ACNEIFORM RASH	1/17 (5.9%)
CUTANEOUS HYPERPIGMENTATION	12/17 (70.6%)
DRY SKIN	2/17 (11.8%)
PAIN OF SKIN	9/17 (52.9%)
PRURITUS	9/17 (52.9%)
RASH/ DESQUAMATION	11/17 (64.7%)
SKIN ULCERATION	1/17 (5.9%)
TELANGIECTASIA	1/17 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.