Study of Stem Cell Transplantation for Hematologic Malignancies Using Clofarabine and Busulfan Regimen

Transplants with stem cells collected from the blood of an unrelated donor (allo-HSCT) are
being used more commonly for many blood cancers which are not curable with more conventional
methods of chemotherapy. Although allo-HSCT has great potential, there are still high risks
due to infections, graft-versus-host disease (GVHD), where the donor's cells attack the
recipient's tissues as foreign, and due to toxic effects of the chemotherapy drugs given to
prepare (or condition) the recipient's bone marrow for transplant.

As a reduced intensity conditioning, a combination of Fludarabine and a lower dose of
Busulfan (Flu/BU2) is one of the most popular regimens. Among full-intensity regimens, a
combination of Fludarabine and standard-dose Busulfan (Flu/BU4) has been investigated
recently and shown to be very well tolerated.

Clofarabine, similar to Fludarabine, is known to have a stronger anti-tumor effect than
Fludarabine and has shown promise in treating aggressive acute leukemias. In addition,
evidence is that it is well-tolerated with manageable side effects especially in older
subjects. Thus replacing Fludarabine with Clofarabine in a full-intensity transplant regimen,
Clo/BU4 may provide a regimen with increased anti-tumor activity without adding significant
risks of toxicity.

The goals of the study are (Phase I) to determine the appropriate dose for Clofarabine with
Busulfan as a full-intensity regimen (Clo/BU4) and then (Phase II) to investigate the safety
and effectiveness of this regimen as a conditioning for HSCT in the treatment for aggressive
hematologic malignancies, in subjects where more conventional approaches are failing.

Inclusion Criteria:

Disease Criteria

- Acute leukemia or chronic myelogenous leukemia in blastic crisis or accelerated phase,
not in remission at the time of transplant

- Myelodysplastic syndrome, with more than 5% blasts in bone marrow at the time of
transplant

- Hodgkin and Non-Hodgkin Lymphomas: Not in CR in PET scan or CT scan before transplant,
or relapsed within 1 year from previous remission

- CLL not in remission

- Multiple Myeloma, not in remission

- Suitable donor available (related or unrelated)

Age, Organ Function Criteria

- Age: ≤ 70 years

- Cardiac: LV Ejection Fraction ≥ 40% by MUGA or Echocardiogram

- Pulmonary: FEV1 and FVC ≥ 40% predicted, and DLCO (corrected for hemoglobin) ≥ 40% of
predicted

- Renal: Adult population: serum creatinine ≤ 1.0 mg/dL (if serum creatinine > 1.0
mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m2
as calculated by the Modification of Diet in Renal Disease equation)

- Renal: Pediatric population: serum creatinine clearance ≥ 90 ml/min/1.73 m2 as
calculated by the Schwartz formula for estimated GFR

- Hepatic: serum total bilirubin ≤ 2.0 mg/dl and AST / ALT ≤ ULN x 4

- Performance status: Karnofsky ≥ 70%

Exclusion Criteria:

- Other active life-threatening cancer requiring treatment other than allo-HSCT

- HIV1 or HIV2 positive

- Uncontrolled medical or psychiatric disorder

- Uncontrolled viral or fungal infection

- Active CNS leukemia

- Non-compliant to medications

- No appropriate caregivers identified