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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 17
- 试验地点
- 4
- 主要终点
- Overall Response Rate
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Carmustine (Drug)
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.
干预措施: Laboratory Biomarker Analysis (Other)
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.
干预措施: O6-Benzylguanine (Drug)
结局指标
主要结局
Overall Response Rate
时间窗: 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
次要结局
- Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity(1 week after the first infusion)
- Changes in the Apoptosis(at 48 hours after the first infusion)
- Changes in the Cell Cycle/Proliferation(at 48 hours after the first infusion)
- Changes in AGT Inactivation in Non-responding Patients(After seventh course at 14 weeks)
- Changes in DNA Damage- Cytotoxicity(48 hours after the first infusion)