Clinical trial NCT00961220: O6-Benzylguanine and Topical Carmustine in Treating Patients With Early-Stage IA-IIA Cutaneous T-Cell Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-08-18
Enrollment: 17
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Overall Response Rate
timeFrame: Up to 2 weeks after completion of study treatment
Secondary outcomes:
measure: Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
timeFrame: Baseline
measure: Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
timeFrame: 24 hours after the first infusion
measure: Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
timeFrame: 48 hours after the first infusion
measure: Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity
timeFrame: 1 week after the first infusion
measure: Changes in the Apoptosis
timeFrame: at 24 hours after the first infusion
measure: Changes in the Apoptosis
timeFrame: at 48 hours after the first infusion
measure: Changes in the Cell Cycle/Proliferation
timeFrame: at 24 hours after the first infusion
measure: Changes in the Cell Cycle/Proliferation
timeFrame: at 48 hours after the first infusion
measure: Changes in DNA Damage- Cytotoxicity
timeFrame: 24 hours after the first infusion
measure: Changes in DNA Damage- Cytotoxicity
timeFrame: 48 hours after the first infusion
measure: Changes in AGT Inactivation in Non-responding Patients
timeFrame: After first course at 2 weeks
measure: Changes in AGT Inactivation in Non-responding Patients
timeFrame: After seventh course at 14 weeks
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Cleveland
country: United States
facility: Case Comprehensive Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Case Comprehensive Cancer Center
name: Kevin Cooper
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tacastacas JD, Chan DV, Carlson S, Gerson SL, Dowlati A, Fu P, Lu K, Groft S, Rosenjack J, Honda K, McCormick TS, Cooper KD. Evaluation of O6-Benzylguanine-Potentiated Topical Carmustine for Mycosis Fungoides: A Phase 1-2 Clinical Trial. JAMA Dermatol. 2017 May 1;153(5):413-420. doi: 10.1001/jamadermatol.2016.5793.