A Phase 3, Randomized, Double-blind Study of Siltuximab (Anti-IL-6 Monoclonal Antibody) or Placebo in Combination With VELCADE and Dexamethasone for the Treatment of Subjects With Relapsed or Refractory Multiple Myeloma

Preclinical and preliminary clinical experience support combining siltuximab
with
VELCADE and dexamethasone in this patient population. In addition, siltuximab
has
been shown to be safe when given in combination with the 3-drug regimen,
VELCADEmelphalan-
prednisone. The VELCADE + low-dose dexamethasone regimen selected as
comparator is a widely used standard of treatment for relapsed or refractory
multiple
myeloma that has shown incremental benefit over VELCADE alone .
VELCADE + low-dose dexamethasone has been well tolerated in dosing
regimens that exceed 1 year of continuous treatment including
studies where VELCADE re-treatment has been offered to previously responding
patients.
This study has been designed to fully evaluate the benefit:risk of
siltuximab when added to the standard regimen of VELCADE + low-dose
dexamethasone

The primary objective of this study is to determine if there is an improvement
in progression-free survival
(PFS) when siltuximab is added to VELCADE* (bortezomib) and dexamethasone in
subjects with relapsed
or refractory multiple myeloma.
The secondary objectives of this study are to assess safety, additional
measures of clinical benefit,
patient-reported outcomes (PROs), pharmacokinetics of dexamethasone and
siltuximab, antibodies to
siltuximab (immunogenicity), exploratory biomarkers, and health economic
outcomes.

This is a randomized, double-blind, placebo-controlled, multicenter Phase 3
study. Approximately
500 subjects with relapsed or refractory multiple myeloma will be randomized
1:1 to receive siltuximab,
VELCADE, and dexamethasone or placebo, VELCADE, and dexamethasone. The primary
endpoint is
PFS according to the European Group for Blood and Marrow Transplantation (EBMT)
criteria (Blade et al,
1998). The final analysis of the primary endpoint PFS will occur when 312
events (disease progression or
death) have been recorded. The final analysis of overall survival will occur
after 280 deaths have been
recorded. This is expected to happen approximately 5 years after the first
subject starts study treatment.
The pharmacokinetics of dexamethasone when given with VELCADE alone, and in
combination with
VELCADE and siltuximab will be determined from approximately 60 subjects
(approximately 30 per
treatment arm) at selected clinical sites. Circulating multiple myeloma cells
(CMMC) will be evaluated
from a minimum of 200 subjects at selected clinical sites.
An Independent Data Monitoring Committee (IDMC) will be established to ensure
the continuing oversight
of the safety of subjects enrolled in this study.

Approximately 500 subjects will be randomized 1:1 using an IVRS to 1 of the
following blinded treatment
arms:
Arm A: Siltuximab, VELCADE, and dexamethasone - repeat every 21 days
- Siltuximab: 11 mg/kg, 1-hour IV infusion, Day 1
- VELCADE: 1.3 mg/m2 IV push, Days 1, 4, 8, 11 for Cycles 1 to 8; then Days 1
and 8 for
Cycle 9 and higher
- Dexamethasone: 20 mg orally, the day of and the day after VELCADE
administration
Arm B: Placebo, VELCADE, and dexamethasone - repeat every 21 days
- Placebo: 1-hour IV infusion, Day 1
- VELCADE: 1.3 mg/m2 IV push, Days 1, 4, 8, 11 for Cycles 1 to 8; then Days 1
and 8 for
Cycle 9 and higher
- Dexamethasone: 20 mg orally, the day of and the day after VELCADE
administration
No crossover between treatment arms will be allowed.

Screening Period: Screening should occur within 21 days before first study
agent administration.
Treatment Period: Treatment will continue until disease progression, death,
unacceptable toxicity despite
dose modification or delays, or withdrawal of consent for study treatment,
whichever occurs first. Subjects
achieving confirmed CR should receive at least 2 additional cycles of the
assigned treatment regimen.
Follow-up Period: All subjects will have follow-up visits 4 weeks (End of
Treatment Visit), 8 weeks, and
12 weeks after the last study agent administration, and thereafter will be
followed up for survival every
3 months until the end of study. For subjects who discontinue study agents
before disease progression,
disease assessments should continue to be performed as scheduled until
confirmed disease progression,
death, the start of a new treatment for multiple myeloma, withdrawal of consent
for study participation, or
the end of study, whichever occurs first. Subjects with disease progression
should be followed up for
subsequent anti-multiple myeloma treatment and survival.
End of study definition: The study will end at the time of the final analysis,
which will be after
280 deaths have been recorded. This is expected to occur approximately 5 years
after the first subject starts
study treatment. Subjects who are benefiting from treatment (complete response
[CR] or partial response
[PR]) at the end of study may be eligible to receive siltuximab in a separate
protocol.

For the risks: see E9 of this document