Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Percentage of Participants With a Minimally Durable Clinical Response Rate
研究概览
简要总结
BACKGROUND:
- Cluster of differentiation 25 (CD25) (p55, Tac or interleukin 2 receptor (IL2R) alpha) is strongly expressed in virtually 100% of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy.
- In ATL, the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14% responses, and the anti-CD52 Mab Alemtuzumab (Campath-1H) produced response lasting greater than 2 months in 30% of 23 patients.
- LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin.
- In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 microg/Kg intravenous (IV) given every other day for 3 doses (every other day (QOD) times 3). LMB-2 induced greater than 90% tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity.
- In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due to reduction of soluble receptor in tumor interstitium.
OBJECTIVES:
-To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting greater than 2 months, which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH).
Secondary objectives:
- To determine the effect of 1 cycle of FC alone in ATL.
- To examine progression-free and overall survival in ATL after FC/LMB-2.
- Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum.
- To study the effects of LMB-2 plus FC on normal B- and T-cell subsets by fluorescence-activated cell sorting (FACS).
ELIGIBILITY:
- CD25 plus ATL, untreated or with prior therapy
- Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC), platelets and albumin at least 1000, 75,000, and 3.0.
DESIGN:
- Fludarabine 25 mg/m(2) IV days 1-3
- Cyclophosphamide 250 mg/m(2) IV days 1-3
- LMB-2 30-40 micro g/Kg IV days 3, 5 and 7.
- LMB-2 dose: Begin with 30 microg/Kg times 3. Escalate to 40 microg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 microg/Kg. Continue at 40 microg/Kg if 0-1 of 6 have DLT at 40 microg/Kg.
- Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
- Accrual goals: 29-37 patients, which includes 4 replacements....
详细描述
BACKGROUND:
- Cluster of differentiation 25 (CD25) (p55, Tac or interleukin receptor 2 (IL2Ra) is strongly expressed in virtually 100 % of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy.
- In adult T-cell leukemia (ATL), the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14 % responses, and the anti-CD52 Mab Alemtuzumab (Campath- 1H) produced response lasting > 8 weeks in of 30 % of 23 patients.
- LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin.
- In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 mcg/Kg dose intravenous (IV) given every other day for 3 doses (every other day (QOD) x3). LMB-2 induced > 90 % tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity.
- In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due reduction of soluble receptor in tumor interstitium.
OBJECTIVES:
-
To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting > 8 weeks which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH).
-
Secondary objectives
-
To determine the effect of 1 cycle of FC alone in ATL.
-
To examine progression-free and overall survival in ATL after FC/LMB-2.
-
Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum.
-
To study the effects of LMB-2 +FC on normal B- and T-cell subsets by FACS.
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
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Fludarabine and Cyclophosphamide/LMB-2
Administer cycle 1 with Fludarabine and Cyclophosphamide (FC) alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
干预措施: LMB-2 (Drug)
Fludarabine and Cyclophosphamide/LMB-2
Administer cycle 1 with Fludarabine and Cyclophosphamide (FC) alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
干预措施: Fludarabine (Drug)
Fludarabine and Cyclophosphamide/LMB-2
Administer cycle 1 with Fludarabine and Cyclophosphamide (FC) alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Percentage of Participants With a Minimally Durable Clinical Response Rate
时间窗: 8 weeks
Response is based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma and must last \>8 weeks to meet the primary endpoint of the study. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion. Stable disease is neither a response nor progressive disease. Progressive disease is appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.
次要结局
- Progression Free Survival (PFS)(70 months)
- Number of Participants With Dose Limiting Toxicity (DLT)(30 days after last dose of LMB2)
- Percentage of Patients Who Developed Neutralizing Antibodies After One or More Cycles of LMB-2(First 24 hours after the dose given on Cycle 2, day 1)
- Duration of Response (Complete Response + Partial Response)(69 months)
- Volume of Distribution of LMB-2(24 hours)
- Count of Participants With Adverse Events Attributed At Least Possibly to Patients Treated With Fludarabine and Cyclophosphamide Dose Levels 20+200, 25+250, and 30+300 mg/m^2(7 years and 12 days)
- Peak Level of LMB-2 in Adult T-Cell Lymphoma(First 24 hours after the dose given on Cycle 2, day 1)
- Overall Survival (OS)(70 months)
- Number of Participants With Serious and Non-serious Adverse Events(7 years and 12 days)
- Soluble Cluster of Differentiation 25 (sCD25) Between Responders and Nonresponders(First 24 hours after the dose given on Cycle 2, day 1)
- Area Under the Plasma Concentration (AUC) - LMB2(First 24 hours after the dose given on Cycle 2, day 1)
- Post Treatment Effects of LMB-2 + Fludarabine and Cyclophosphamide (FC) on Normal B and T Cell Subsets by Flow Cytometry(First 24 hours after the dose given on Cycle 2, day 1)
- Plasma Clearance (CL) of LMB-2(First 24 hours after the dose given on Cycle 2, day 1)
- Half Life (t1/2) of LMB-2(First 24 hours after the dose given on Cycle 2, day 1)
- Count of Participants With Grades 3-5 Adverse Events of > 1 Adult T-Cell Leukemia (ATL) Patients Treated With 20+200, 25+250, and 30+300 mg/m^2 LMB-2/Fludarabine and Cyclophosphamide(7 years and 12 days)
研究者
Robert Kreitman, M.D.
Principal Investigator
National Cancer Institute (NCI)