PHASE II TRIAL EXAMINING MULTIPLE IV INFUSIONS OF FOUR DOSES OF ABX C

这是一项第二阶段、多中心、开放标签、剂量递增的临床试验，研究在类固醇耐药的急性移植物抗宿主病(GVHD)患者中多次输注四种剂量的ABX-CBL。在100天内接受干细胞移植的儿童和成人，在改良的IBMTR严重程度量表上严重指数为B、C或D的类固醇抗药性急性移植物抗宿主病可能有资格参与这项研究。共有48名患者，每个治疗队列12名，将在美国境内的6到10个临床地点参加这项研究。威斯康星大学可能会邀请多达10名患者参加。患者将每天输注ABX-CBL，连续七天(诱导方案)，然后维持每周两次输液方案，持续两周。所有队列中的患者将接受最多11次ABX-CBL静脉输注。研究药物将通过注射器泵在两个小时内输注。安全评估将在进入下一个队列之前进行。四个队列如下：队列1：0.01 mg/kg；队列2：0.1 mg/kg；队列3：0.3 mg/kg；队列4：1.0 mg/kg。为了安全和临床效果，患者将被跟踪8周(每周访问4周，然后访问4周)。安全性将通过监测研究中的不良事件以及注射ABX-CBL期间的生命体征、频繁的体检、实验室研究包括完整的血细胞计数、T细胞亚群、血清化学和定期尿液分析来评估。所有患者将获得基线CPK和同工酶，有输液相关不良经历的患者将获得重复的CPK和同工酶。此外，将通过酶联免疫吸附试验监测患者的人类抗鼠抗体(HAMA)反应。ABX-CBL的临床效果将通过评估急性移植物抗宿主病(GVHD)总体评分的变化来评估，该评估基于修改的IBMTR严重性指数、反应时间、反应持续时间、急性移植物抗宿主病发作的时间和发生率以及住院时间。每个队列中的5名患者将被分配进行药代动力学血样以进行PK图谱。PK的任务将是结合每个队列中的前五名患者，并尝试在男性和女性以及成人和儿科之间平均分配。接受过至少一次ABX-CBL输注的患者将被安排参加一项长期随访计划，以评估ABX-CBL的长期安全性和长期存活率。

This is a Phase II, multicenter, open label, dose escalation clinical trial examining multiple infusions of four doses of ABX-CBL in patients with steroid-resistant acute Graft Versus Host Disease (GVHD). Children and adults receiving a stem cell transplant within 100 days, with steroid resistant acute GVHD with a severity index of B, C, or D on the modified IBMTR Severity Scale may be eligible to participate in this study. A total of 48 patients, 12 per treatment cohort, will be enrolled in this study at six to ten clinical sites within the United States. Up to ten patients may be invited to participate at the University of Wisconsin. Patients will be infused with ABX-CBL daily for seven days (induction regimen) followed by a maintenance regimen of infusions two times per week for two weeks. Patients in all cohorts will receive up to eleven intravenous infusions of ABX-CBL. The study medication will be infused over two hours via a syringe pump. Safety evaluations will occur prior to advancing to the next cohort. The four cohorts are as follows: Cohort 1: 0.01 mg/kg; Cohort 2: 0.1 mg/kg; Cohort 3: 0.3 mg/kg; Cohort 4: 1.0 mg/kg. Patients will be followed for eight weeks (visits are weekly for four weeks followed by a visit four weeks later) for safety and clinical effect. Safety will be assessed by monitoring adverse events while on study as well as vital signs during the infusion of ABX-CBL, by frequent physical exams, laboratory studies including complete blood counts, T-cell subsets, serum chemistries, and urinalyses at regular intervals. Baseline CPK with isoenzymes will be obtained on all patients and patients who experience any infusion related adverse experiences will have repeat CPK with isoenzymes obtained. In addition, patients will be monitored for Human Anti Mouse Antibody (HAMA) response by ELISA. Clinical effect of ABX-CBL will be assessed by evaluating changes to the overall score of acute GVHD based upon a modified IBMTR Severity Index, time to response, duration of response, time and incidence of flare of acute GVHD, and length of hospitalization. Five patients in each cohort will be assigned to have pharmacokinetic blood samples for pK profile. The assignment to pK will be a combination of the first five patients in each cohort and the attempt to evenly distribute between males and females and adults and pediatrics. Patients who have received at least one infusion of ABX-CBL will be scheduled to participate in a long-term follow-up program to evaluate the long term safety of ABX-CBL and long term survival.