An open-label, multi-center, three arm randomized, phase III study to compare the efficacy and safety of RO5072759 + chlorambucil (GClb), rituximab + chlorambucil (RClb)or chlorambucil (Clb) alone in previously untreated CLL patients with comorbidities.

In the recent past, first-line treatment of CLL has developed from single-agent
therapy with alkylating drugs (e.g. chlorambucil [Clb]) to modern combination
therapy incorporating purine analogues (i.e. fludarabine, pentostatin,
cladribine) and monoclonal antibodies (i.e. rituximab, alemtuzumab). Currently,
immunochemotherapy with fludarabine, cyclophosphamide and rituximab (FCR) is
the standard of care in previously untreated patients with CLL requiring
treatment.
The majority of CLL patients are more than 65 years old. Such elderly patients
are frequently compromised by concurrent pathological conditions and/or
physiological decline of organ function.
Since elderly and medically unfit patients have been under represented in
clinical trials, it is unclear how these patients should be managed at best.
Immunochemotherapy with FCR is often withheld from medically unfit patients
because co morbid conditions and age-related changes of the organ function may
facilitate the occurrence and increase the severity of sustained cytopenia,
T-cell depletion and opportunistic infections. Low-dose FCR has been reported
to reduce the risk of neutropenia without lowering the response rate. However,
use of such a regimen was associated with significant shortening of the
progression-free survival and has not been evaluated in elderly or medically
unfit patients so far.
CLL patients considered to be ineligible for fludarabine-based
immunochemotherapy due to co morbidity and/or other age-related problems are
frequently treated with the alkylating drug chlorambucil. Although chlorambucil
is generally well tolerated, complete responses are rare and remission
durations are usually shorter than 1.5 years.
Alternative immunotherapeutic regimens combining cytostatic drugs and
monoclonal antibodies have not been investigated in the medically unfit yet.
Specifically, the combination of chlorambucil as a standard of care in such
patients with CD20 antibodies warrants to be explored in a randomised fashion.

The primary objective of the study is to demonstrate clinically relevant
statistical superiority in progression-free survival (PFS) with GClb compared
to RClb and Clb alone and RClb compared to Clb [GClb vs Clb; GClb vs RClb; RClb
vs Clb] in previously untreated CLL patients with co morbidities.

Phase III, open-label, multi-centre, three-arm randomized, parallel group
comparative study.
Patients will receive up to 6 months of study treatment.
Patients who cross-over treatment arms may receive an additional 6 months of
study treatment (maximum of 12 months).
Recruitment duration: Approximately 3 years
Follow-up for disease progression: 5 years from last patient enrolled
Follow-up for survival: 8 years from last patient enrolled
Total study duration will be approximately 12 years.
The end of study is defined as 8 years after the last patient was enrolled
(unless all patients have died).
See also Figure 2 on page 42 of protocol BO21004 version B, 24 August 2009

Treatment Arm A (GClb):
RO5072759: 1000 mg (flat dose) iv infusion
Cycle 1: Day 1 , 8 and 15
Cycle 2 - 6: Day 1
+ Chlorambucil: 0.5 mg/kg body weight po, day 1 and 15 of each cycle

Treatment Arm B: (RClb):
Rituximab: iv infusion on day 1 of each cycle
Cycle 1 : 375mg/m2
Cycles 2 - 6 : 500mg/m2
+ Chlorambucil: 0.5 mg/kg body weight po, day 1 and 15 of each cycle

Treatment Arm C (Clb):
Chlorambucil: 0.5 mg/kg body weight po, day 1 and 15 of each cycle

The following assessments will be done: intravenous administration of
medication, oral administration of medication, physical examination, blood
pressure, pulse, blood collection, pregnancy test (if relevant), ECG, CT scan,
bone marrow collection (if required) and questionnaires (EORTC QLQ-C30, EORTC
QLQ-CLL16).

Blood collection can cause hemorrhages and discomfort at the site of blood
draw. There is also a risk of infection at the site of blood collection.
Patients will be exposed to radiation by CT-scans, but the risk is very small.
There is a small risk that patients experience a reaction to the contrast agent
that is injected for a CT scan.
For bone marrow collection, there is a risk of pain, discomfort and (in rare
occasions) infection of the site of bone marrow collection.

Rituximab and RO5072759 can cause infusion reactions, that can result in fever,
chills, tremors, blisters and itching, nausea, fatigue, head ache, difficulty
breathing, swelling of tongue and throat, vomiting, redness in neck and face,
irregular heartbeat, tumorpain. There is also an increased risk of infection
associated with the use of rituximab and RO5072759.
Chlorambucil can cause decreased production of white blood cells, platelets and
red blood cells in the bone marrow, nausea, vomiting, diarrhea and mouth
ulcers. Decreased white blood cells can result in increased risk of infections,
decreased platelets can result in prolonged bleeding, and decreased red blood
cells can lead to fatigue and shortness of breath.

RO5072759 or rituximab can cause allergic reactions.

Unknown adverse reactions can occur.