An Open Label Phase I Trial of Alemtuzumab (Campath 1-H) Therapy for Refractory Chronic Graft-vs-Host Disease

This is a phase I, dose escalation trial of alemtuzumab for patients with steroid-refractory chronic GVHD. Alemtuzumab will be given over a 4-week period.

Three escalating doses of alemtuzumab will be considered to determine the maximum tolerated dose (MTD). In this design, a cohort of 3-6 patients will be treated at each dose level. Dose-limiting toxicity (DLT) will be defined as any life-threatening anaphylaxis due to an alemtuzumab infusion, any grade 4 non-hematologic toxicity directly related to alemtuzumab during the 12 week assessment period, any grade 4 hematological toxicity, and any grade 4 infectious complication that requires hospitalization. CMV reactivation secondary to alemtuzumab is an expected complication of alemtuzumab and will not be considered a DLT unless grade 4 CMV disease occurs. CMV DNA levels will be closely monitored and preemptive therapy for CMV will be initiated if there is evidence of CMV reactivation.

Three patients will be entered at each dose level. The dose of alemtuzumab will be escalated if these 3 patients complete the 4-week treatment and none experience a DLT by week 12 of therapy. If 1 of 3 patients treated at a given dose level experiences a DLT, then 3 more patients are treated at that dose level. If the incidence of DLT among those 6 patients is 1 in 6, then dose escalation to the next highest dose level occurs. If 2 or more of the 6 patients treated at a dose level experience DLT, then the MTD is considered to have been exceeded. At that point, unless 6 patients were treated at the previous dose level, 3 further patients will be treated at that level, and the same principles for determination of the MTD apply. There will be no further dose escalation at this point, and the MTD will be the dose level at which no more than 1/6 subjects experience a DLT. Once 6 patients have been treated at the MTD, an additional 10 patients will be treated at that dose level to further delineate toxicity and efficacy at that dose level.

Patients who experience either no toxicity, grade I-II toxicity that has resolved by the time of clinical response assessment and who have had no response or only a partial response to therapy can receive a second course of alemtuzumab after week 12. The second course of alemtuzumab will be a 4-week course at the same dose and schedule as the first course of treatment. Patients who have complete response and resolution of their chronic GVHD will not be retreated regardless of toxicity. Patients with any grade IV toxicity will not be retreated regardless of their response. Toxicity associated with second courses of therapy will not be used in the assessment of the MTD.

Toxicity assessments will be ongoing and recorded at scheduled clinical visits. Clinical response assessments will be done by assessing the presence or absence of signs and symptoms of GVHD after completion of 3 months on the study, during week 12. A similar series of immunologic assays will be performed on subjects enrolled on this clinical trial as in Specific Aim 1.