A Multicenter, Randomized, Double-Blind, Placebo Controlled Phase 2 Study of LY2127399 in Combination with Bortezomib and Dexamethasone in Patients with Previously Treated Multiple Myeloma

Despite treatment advances over the past decade, multiple myeloma (MM) remains
an incurable
malignancy. Bortezomib is an established foundational therapy as a single agent
and with
dexamethasone, and shows promise with other agents, including melphalan and
prednisone in the
first-line setting. New agents against novel targets, particularly those
hypothesized to mediate
treatment resistance, are needed, and further improvements in MM therapy will
require targeting
multiple pathways to increase responses and prolong disease control. B-cell
activating factor
(BAFF) stimulation through its receptors causes NFkappaB (NF-*B) pathway
activation and
resistance to apoptosis mediated by cancer therapies. BAFF levels appear to be
elevated in
patients with MM, and data from a preclinical model of MM suggested that
targeting BAFF may
result in antimyeloma activity and inhibit osteoclastogenesis. Data from Phase 1
Study H9S-MC-JDCF (JDCF) suggest that the combination of bortezomib and
LY2127399
(tabalumab) is well-tolerated and active in the relapse setting. The
pharmacokinetic (PK) profile
of tabalumab stabilizes at doses of approximately 100 mg and above; however, a
recommended
dose has not been determined. Study H9S-MC-JDCG (JDCG) will establish the
recommended
dose of tabalumab to be used in combination with standard doses of bortezomib
and
dexamethasone in patients with MM and subsequently establish whether the
addition of
tabalumab to bortezomib and dexamethasone improves the progression-free
survival (PFS) of
patients with relapsed or refractory MM treated with at least 1 but not more
than 3 prior lines of
therapy.

The primary objective is to compare PFS after treatment with tabalumab,
bortezomib, and
dexamethasone to that of placebo, bortezomib, and dexamethasone in patients
with relapsed/refractory MM.

Secondary objectives will include comparison of treatment and placebo arms for
assessment of:
Quality of response (QoR)
* Best overall response (BOR)
* Overall survival (OS)
* Time to progression (TTP)
* Time to next treatment (TNT)
* Duration of response (DOR)
* Time to first skeletal-related event (SRE)
* The incidence of clinically significant pain response
* To describe the population PK of tabalumab in patients with MM
* To describe the immunogenicity of tabalumab in patients with MM

The exploratory objectives of the study are as follows:
* Biomarker objectives may include some combination of the following, depending
on the evolving science:
o determine whether serum BAFFand/or a proliferation-inducing ligand (APRIL)
levels are associated with percent change from baseline in the
difference between involved and uninvolved serum free light chains (SFLC),
objective response, and
response duration
o determine whether mutations in genes including, but not limited to, the
NF-*B pathway in bone
marrow cells predict response to therapy that includes tabalumab
o determine whether the RNA expression of genes included in, but not limited
to, the BAFF and
NF-*B pathways in bone marrow cells predicts response to therapy that includes
tabalumab
o determine whether SNPs near different genes reported to affect multiple
myeloma response, including BAFF, B-cell activating factor receptor (BAFF-R),
transmembrane
activator and calcium-modulator and cyclophilin ligand interactor (TACI), or
B-cell maturation
(BCMA) in germline or bone marrow cell DNA predict response to therapy that
includes tabalumab
o determine whether surface expression of BAFF-R, TACI, or BCMA on bone marrow
plasma cells
predicts response to therapy that includes tabalumab
o determine whether the percent change in the difference between the involved
and uninvolved
SFLC accurately predicts response faster than standard assessments
* Health outcomes objectives
o To compare the health status, health-related quality of life, and resource
utilization between the
treatment arms

This is a multicenter, randomized, double-blind, placebo-controlled, 3-arm
Phase 2 study of
bortezomib and dexamethasone with placebo or tabalumab (100 mg or 300 mg) in
patients with relapsed/refractory
MM previously treated with 1 to 3 lines of therapy.
The study is designed to evaluate the effect of tabalumab in combination with
bortezomib, and dexamethasone in
patients with relapsed/refractory MM.
Approximately 213 patients will be randomized to 1 of the 3 treatments at a
1:1:1 ratio.
Patients will receive treatment for 8 cycles unless they meet a condition for
treatment discontinuation. Efficacy
will be measured prior to each new cycle of therapy. Patients who are receiving
measureable benefit at Cycle 8
may receive up to 2 additional cycles. The final database lock will occur after
140 PFS events have been observed
such that the final survival analysis may be performed.

Reference Therapy, Dose, and Mode of Administration:
Arm A:
Dexamethasone 20 mg administered orally (po) Days 1, 2, 4, 5, 8, 9, 11, and 12
for 8 cycles
Placebo administered intravenously (IV) over 30 minutes every 21 days for 8
cycles
Bortezomib 1.3 mg/m2 Days 1, 4, 8, and 11 administered subcutaneously (SQ)
every 21 days for 8 cycles
Test Product, Dosage and Mode of Administration:
Arm B:
Dexamethasone 20 mg po Days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days for 8
cycles
Tabalumab100 mg administered IV over 30 minutes every 21 days for 8 cycles
Bortezomib 1.3 mg/m2 Days 1, 4, 8, and 11 administered SQ every 21 days for 8
cycles
Arm C:
Dexamethasone 20 mg po Days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days for 8
cycles
Tabalumab 300 mg administered IV over 30 minutes every 21 days for 8 cycles
Bortezomib 1.3 mg/m2 Days 1, 4, 8, 11 administered SQ every 21 days for 8
cycles

There are risks associated with the use of the study drug tabalumab and the
comparators bortezomib and dexamethasone. Please refer to attachment 3 of the
patient information leaflet. There are also risks associated with the study
procedrues: X-rays, CT scans (reaction to contrast), MRI (metal objects in the
body; claustrophobia), and there may be complications or infections due to
punctions (blood tests), IV injections, subcuteneous injections, bone marrow
biopsy/aspirate. These are elucidated in attachment 3 of the patient
information. In addition, the study medication and other drugs required by the
protocol, the procedures and their combination may have other unknown risks.
The patient taking part does not necessarily benefit from this study. Knowledge
derived from this study may benefit patients in the future.