Trial Information

A Prospective, Multi-center Phase II Study of Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Stem-cell Transplantation, in Chronic Lymphocytic Leukemia Which is Associated With 17p Deletion or is Refractory to Fludarabine

CLL refractory to therapy based on fludarabine or with 17p deletion has a poor prognosis.
Patients with F-refractory CLL have a remission rate of 20% after various salvage regimens
and a median overall survival (OS) of <12 months (Keating et al., 2002a). CLL patients with
17p deletion have a median OS of 16 months after first-line treatment with fludarabine or FC
in the CLL4 trial of the GCLLSG (Figure 2; Stilgenbauer et al., 2005b; Eichhorst et al.,
2006).

Alemtuzumab is the most active single agent in fludarabine-refractory CLL, with remission
rates of 30-40% and median OS of 16-28 months (Keating et al., 2002b, Rai et al., 2002).
Furthermore, alemtuzumab is of proven efficacy in CLL with 17p deletion and the subcutaneous
administration is as effective as the intravenous application (Stilgenbauer & Döhner, 2002,
Lozanski et al., 2004, Stilgenbauer et al., 2004).

However, the outcome of fludarabine-refractory CLL is still poor, owing to the facts that
the majority of patients do not achieve a remission and that the average duration of
remission is short. Therefore, the current trial aims at achieving: (i) a higher remission
rate, by adding high-dose dexamethasone to alemtuzumab, and (ii) prolongation of remission
duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation
(SCT). High-dose steroids have shown activity independently of 17p and p53 status, and are
effective in debulking large lymph nodes, a weakness of alemtuzumab (Bellosillo et al.,
2002, Thornton et al., 2003, Pettitt et al., 2006). Maintenance treatment with alemtuzumab
improved remission duration in the CLL4B trial and allogeneic SCT resulted in disease
control in high-risk CLL in the CLL3X trial (Wendtner et al., 2004, Dreger et al., 2005).

This is a prospective, open, multi-center Phase II study conducted by the Deutsche CLL
Studiengruppe (DCLLSG; German CLL Study Group, GCLLSG). There will be only one treatment
group and thus no randomization. The study will be conducted at approximately 40
investigation sites in Germany, Austria and France.

The study will be conducted according to the EG Directive on Good Clinical Practice, the
German Arzneimittelgesetz (AMG, 12. Novelle) as well as - with respect to the local
activities and regulations - to the corresponding laws in France and Austria.

A total of 122 patients (adults, males and females, in-patients and out-patients; 2 to 10
patients are expected to be recruited by each of the centers) will be recruited, with
stratification by detailed diagnosis. The distribution of female and male patients is not
relevant for the study as both sexes are affected by CLL and treatment effects are not
different in both groups (GCP-V § 7, 2). Recruiting will stop when the 122th. patient has
completed the first four-week cycle of treatment. The study will be concluded when the last
patient has completed treatment with alemtuzumab according to this protocol. The retrieval
of additional follow-up data may be appropriate to achieve mature data in the survival
endpoints.

Subcutaneous alemtuzumab (30 mg) will be administered three times weekly (days 1, 3 and 5)
along with oral dexamethasone (40 mg/day, days 1-4, every 2 weeks) for at least 4 weeks
(corresponding to 12 doses of alemtuzumab, in case of treatment interruption this may take
longer than 4 weeks) and, for patients who show at least SD, a maximum of 12 weeks (36 doses
of alemtuzumab, in case of treatment interruption this may take longer than 12 weeks).
Thereafter, maintenance therapy with alemtuzumab will be instituted for a maximum of two
years. If CR (including bone marrow histology and imaging (chest X-ray and ultrasound, CT if
indicated) is documented before week 12, i.e. after week 4 (12 doses of 30 mg alemtuzumab)
or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with alemtuzumab will be
instituted at this time point.

In this study it is recommended to start the dose of alemtuzumab directly at 30 mg. However,
the dose of alemtuzumab can be increased gradually (3 mg day -2, 10 mg day -1 and 30 mg day
1, as in earlier studies), according to the investigators discretion.

Staging will be performed at inclusion to the study and after 12 doses of alemtuzumab (aim:
at the end of Week 4), after 24 doses of alemtuzumab (aim: at the end of Week 8), and after
36 doses of alemtuzumab (aim: at the end of Week 12) of treatment. Patients showing
progressive disease (PD) (according to NCI criteria) will be withdrawn from the study. If
hematological or other toxicity is seen, treatment will be interrupted and the dose will be
reduced according to the prescription information.

If after 12 weeks there is stable disease (SD), partial response (PR) or complete response
(CR), then maintenance treatment will be given, with continued subcutaneous alemtuzumab (30
mg every 14 days). Patients for whom stem-cell transplantation is a realistic treatment
option will be offered the possibility of receiving allogeneic stem-cell treatment in
another clinical trial (CLLX2 or other GCLLSG trial). The latter will however only be
offered if (1) the patient is eligible according to protocol and (2) a HLA-compatible donor
is available who has given his/her informed consent. There should be a treatment-free period
of at least 2 months before SCT, details are specified in the corresponding protocol.

Appropriate premedication and infection prophylaxis will be administered. After each disease
staging (i.e. every three months during the maintenance phase), if there is SD, PR or CR,
then patients will continue study therapy (alemtuzumab maintenance). Maintenance therapy
will be stopped after two years.

During the study, continual monitoring of efficacy and toxicity will be performed. Early
stopping rules will be applied if major intolerability is observed.

Response will be assessed by clinical examination, blood counts, clinical chemistry, chest
X-ray (plain radiograph of the chest), ultrasound of the abdomen, CT scanning (if
indicated), bone marrow cytology and histology (only in cases of possible CR), and
assessment of MRD (for molecular response rate only). Time points for response evaluation
according to NCI criteria will be after 12 doses, 24 doses, and 36 doses of alemtuzumab. For
an uninterrupted treatment course, this will be after 4, 8 and 12 weeks respectively. (If
treatment with alemtuzumab is interrupted, then the time points for all subsequent doses,
assessments and other procedures will be delayed correspondingly; i.e., the number of doses
is the determining factor for elapsed treatment time, and not the calendar date; see above,
"Staging will be performed...".) Follow-up assessment will continue at three-month intervals
for at least three years.

The following time schedule is anticipated for the study:

- Start of recruitment: January 2008

- End of recruitment: September 2011

- End of study procedures (conclusion of maintenance therapy): December 2013 (plus
eventual additional follow-up)