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

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ClinicalTrials.gov Identifier: NCT00961220
Recruitment Status : Completed
First Posted : August 18, 2009
Results First Posted : March 23, 2015
Last Update Posted : May 22, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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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:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
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 : February 1, 2010
Actual Primary Completion Date : April 8, 2012
Actual Study Completion Date : April 8, 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Carmustine

Arms and Interventions
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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
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Primary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00961220


Locations
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United States, Michigan
Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, Ohio
Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106-5065
Case Western Reserve University
Cleveland, Ohio, United States, 44106
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kevin Cooper Case Comprehensive Cancer Center
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00961220    
Other Study ID Numbers: NCI-2012-02927
NCI-2012-02927 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
3405
CASE 3405-CC304 ( Other Identifier: Case Comprehensive Cancer Center )
7080 ( Other Identifier: CTEP )
P30CA043703 ( U.S. NIH Grant/Contract )
R21CA115057 ( U.S. NIH Grant/Contract )
U01CA062502 ( U.S. NIH Grant/Contract )
First Posted: August 18, 2009    Key Record Dates
Results First Posted: March 23, 2015
Last Update Posted: May 22, 2018
Last Verified: April 2018
Additional relevant MeSH terms:
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Mycoses
Lymphoma
Lymphoma, T-Cell
Mycosis Fungoides
Sezary Syndrome
Lymphoma, T-Cell, Cutaneous
Syndrome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
 Disease
Pathologic Processes
Lymphoma, Non-Hodgkin
Bacterial Infections and Mycoses
Infections
Carmustine
O(6)-benzylguanine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors