Trial Information

A Phase I/II Study of Alemtuzumab and Clofarabine for Relapsed or Refractory Acute Lymphoblastic Leukemia

The strategy for treating relapsed and refractory adult ALL patients is through reinduction
chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of
the salvage regimen is acceptable. However, this leukemia is characterized as being highly
refractory to standard chemotherapy and therefore novel therapeutic approaches are
desperately needed. Clofarabine is a second generation nucleoside analog FDA approved for
the treatment of relapsed and refractory pediatric ALL. Clofarabine has been administered
to adult patients with hematologic malignancies with an acceptable toxicity profile with 8%
of relapsed ALL patients attaining a complete response (CR). The maximum tolerated dose
(MTD) of clofarabine IV in adult patients has been determined to be 40 mg/m2/day for 5
consecutive days, which is lower than the tolerable daily dose for pediatric patients, 52
mg/m2/day. More recently, Karp and colleagues reported their experience with clofarabine in
combination with cyclophosphamide in 18 patients with refractory acute leukemias.
Encouraging responses were seen in the refractory ALL patients with 67% (4/6) patients
experiencing a CR. Toxicity did not allow dose escalation of clofarabine and the MTD was
defined as 10 mg/m2 administered over 6 non-consecutive days when combined with
cyclophosphamide 200-400mg/m2 over a total of 7 days per cycle. As such, we are
conservatively evaluating a clofarabine dose of 20mg/m2 for five days with a dose
de-escalation step if there is dose limiting toxicity.

The addition of monoclonal antibody therapy is an attractive approach in the treatment of
relapsed and refractory ALL since it targets both B and T progenitor ALL subtypes and has
different mechanisms of action and side effects than chemotherapy. Alemtuzumab is a
humanized monoclonal antibody to CD52 which is expressed on the majority of neoplastic
lymphocytes, including 70% of ALL and 100% of Philadelphia positive ALL. The CALGB
evaluated alemtuzumab as consolidation in front-line therapy for patients with ALL and
demonstrated feasibility and found alemtuzumab administration at 30mg subcutaneously
administered for 12 doses to be safe and well tolerated in a frontline consolidation setting
in ALL. In the present protocol targeting refractory and relapsed ALL patients, the maximal
alemtuzumab dose will be 30 mg as in Stock's study, but will be administered intravenously
in order to improve the induction chemotherapy pharmacokinetics. Premedication with
dexamethasone, benadryl, and acetaminophen will be given to all patients prior to
alemtuzumab infusion to prevent infusional reactions associated with intravenous dosing.

The combination of purine analogs and alemtuzumab have been administered simultaneously
safely with promising additive activity in other relapsed and refractory lymphocytic
leukemias. A recent case series reported patients with relapsed and/or refractory ALL who
failed several induction chemotherapies to achieve complete responses to fludarabine and
alemtuzumab combination regimens. All patients were able to proceed to allogeneic SCT with
refractory ALL patient relapsing at 8 months while relapsed patients remain in remission at
6 and 24 months.

Other approaches utilizing combination chemotherapy have failed to demonstrate consistent
activity that would qualify them as standard of care. Therefore the standard of care for
patients with relapsed and refractory ALL is enrollment into clinical trials.

All patients will receive alemtuzumab in a dose escalation fashion (3, 10, 30mg).
Successive escalating doses will be administered if the previous dose is tolerated.
Previously, Stock et al established the safety of 12 doses of 30mg of alemtuzumab in ALL.
The treatment regimen is designed to have alemtuzumab administered prior to administration
of clofarabine to allow dose escalation of the monoclonal antibody and decrease confounding
acute toxicities such as infusion reactions and cytokine release. Clofarabine dose is
modeled after previous trials in adult and pediatric ALL. The starting dose of clofarabine
is lower than standard phase II doses for adult hematologic malignancy to conservatively
evaluate tolerability and toxicity of clofarabine in combination with alemtuzumab.
Alemtuzumab dosing will be limited to a total of 12. However, patients can continue with
additional cycles of clofarabine if they do not show progressive disease or have
unacceptable toxicity.