Precision Dosing of Alemtuzumab

The hypothesis is that the model-informed dosing regimen will prospectively allow the
precision dosing of alemtuzumab to target Day 0 levels to fall between 0.15-0.6ug/mL in
greater than 80% of patients. The investigators have chosen a conservative pilot study
approach, and the aim is to achieve Day 0 alemtuzumab levels between 0.15-0.6ug/mL in greater
than 60% of 20 patients enrolled in this pilot study based on a Simon two-stage design as
detailed below.

A Simon two-stage design (Simon, 1989) is being used. The null hypothesis that 30% of
patients will achieve a Day 0 alemtuzumab level between 0.15-0.6ug/mL will be tested against
a one-sided alternative that the alemtuzumab dose modification will result in 60% of patients
achieving a Day 0 alemtuzumab level between 0.15-0.6ug/mL. In the first stage, 7 patients
will be accrued. If there are 2 or fewer patients that achieve Day 0 alemtuzumab levels
within the range of 0.15-0.6ug/mL, the study will be stopped. Otherwise, 13 additional
patients will be accrued for a total of 20. The null hypothesis will be rejected if 11 or
more patients achieve a Day 0 level of 0.15-0.6ug/mL within the total 20 patients. This
design yields a type I error rate of 0.04 and power of 0.82 when the true response rate is
0.60. The investigators will enroll up to 30 patients in order allow for subject withdrawal,
but will stop enrollment once 20 patients reach Day 0.

Inclusion Criteria:

1. Patients who are undergoing RIC HCT with alemtuzumab, fludarabine, and melphalan at
CCHMC for treatment of a non-malignant disease.

2. Age ≥ 6 weeks to ≤ 30 years (at time of enrollment).

3. For the first 7 patients, patients must have a 10/10 HLA matched related or unrelated
stem cell donor, or be receiving a CD34+ selected stem cell product. After the first 7
patients, any donor match may be allowed after data review by the PI and medical
monitor.

Exclusion Criteria:

1. Patients with a history of anaphylaxis to alemtuzumab.

2. Patients who have previously received alemtuzumab and have not cleared alemtuzumab
prior to the start of the preparative regimen.

3. Life expectancy less than 2 weeks.

4. Patients receiving dialysis.

5. Failure to sign informed consent and/or assent, or inability to undergo informed
consent process.

6. It is not medically advisable to obtain the specimens necessary for this study.

7. Not able to tolerate subcutaneous dosing (patients with severe skin conditions such as
epidermolysis bullosa).