Trial Information

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.

Eligible patients will have undergone allogeneic stem cell transplantation using
myeloablative or non-myeloablative conditioning regimens at least 180 days (6 months) ago.
Patients must have steroid refractory chronic GVHD, defined as having persistent signs and
symptoms of chronic GVHD despite the use of prednisone at >0.5 mg/kg/day or 1 mg/kg every
other day for at least 4 weeks in the preceding 12 months (or equivalent dosing of alternate
corticosteroids) without complete resolution of signs and symptoms. Patients with either
extensive chronic GVHD or limited chronic GVHD requiring systemic therapy are eligible.
Subjects must be on stable doses of immunosuppressants and corticosteroids for 4 weeks prior
to enrollment, and the dose of corticosteroids must be less than 2mg/kg/day prednisone use
(or equivalent). Subjects will be required to have adequate bone marrow and organ function
at the time of enrollment.