Trial Information

Subcutaneous Injection, Low Dose Alemtuzumab for Consolidation and Maintenance of Patients in Clinical Response After Having Achieved Partial or Complete Remission After 1st or 2nd Line Anti-Tumor Therapy for B-Cell CLL

Fludarabine (F) alone or in combination with cyclophosphamide (FC) is not a curative
treatment for patients with CLL, all patients will eventually relapse. Therefore there is a
medical need to look for consolidation followed by maintenance therapies which are able to
prolong response duration or which can shift anti-tumor therapy induced partial remissions
to complete remissions or eradicate minimal residual disease in complete - but still
PCR-positive – responders.

There is no standard consolidation therapy available at the moment and the role of
consolidation in CLL has recently been acknowledged as a research field of major importance
in B-CLL (Schering global advisory board meeting, Lisbon Nov 2005). Possible treatment
options are high-dose chemotherapy followed by autologous stem cell transplantation (the
role of which however remains uncertain with lack of worldwide consensus) or monoclonal
antibody therapy against antigens expressed by CLL cells. Alemtuzumab is directed against
the CD52-antigen which is present in high density on CLL cells and may therefore be most
suitable for treatment of residual disease.

Alemtuzumab has shown significant remission rates in patients with fludarabine refractory
CLL and sub analysis revealed a very high effectiveness of the antibody in clearing CLL
cells from peripheral blood and bone marrow. These findings suggest that Alemtuzumab might
be an ideal candidate to eliminate minimal residual disease in a post-remission treatment
after anti-tumor therapy and to be used as maintenance therapy. The efficacy of Alemtuzumab
as consolidation therapy in CLL can easily be measured. There is evidence from several
studies that treatment with Alemtuzumab does not have a negative impact on stem cell
mobilization. Therefore, autologous stem cell transplantation still remains as a further
treatment option for those patients who still have detectable disease after primary
cytoreduction followed by consolidation therapy with Alemtuzumab.

Side effects of s.c. Alemtuzumab in heavily pretreated patients with advanced disease are
tolerable and manageable. Data have suggested that the safety profile of this antibody is
even more favorable in less pretreated patients and the GCLLSG study suggests that a
wash-out period of more than 8 weeks and possibly also a lower dose is necessary to avoid
severe infectious problems. Campath administration started after a 2-month wash out period
after Fludarabine was shown to be feasible and good tolerated. Based on the collective data
obtained from other pilot or phase II studies, a subcutaneous consolidation dose of 30 mg
once weekly in previously treated and untreated CLL patients after an induction with
Fludarabine combination seems to be a safe and effective dose.

The proposed study aims to evaluate the efficacy of low dose treatment with Alemtuzumab with
regard to the following questions: Does consolidation therapy with low dose Alemtuzumab
result in a prolonged time to disease progression in comparison to patients who do not
receive further treatment? Is it possible to turn a PR into a CR? Does maintenance therapy
with Alemtuzumab translate into a progression-free survival benefit compared to patients
with no further treatment? How is the safety profile in patients treated with low dose
Alemtuzumab as MRD elimination and as maintenance therapy?