Trial Information

An Open-label Phase II Study of the Efficacy of Combination Bortezomib-containing Regimens in the Treatment of Newly Diagnosed Patients With t (4; 14) Positive Multiple Myeloma

PROTOCOL SYNOPSIS A. TITLE: An Open-Label Phase II Study of the Efficacy of Combination
Bortezomib-containing Regimens in the Treatment of newly diagnosed patients with t (4;14)
positive Multiple Myeloma.

B. RATIONALE: Between 15 and 20% of myeloma patients exhibit a t(4;14), which results in
translocation of the receptor tyrosine kinase (TK) fibroblast growth factor receptor 3
(FGFR3) from chromosome 4 to the IgH locus. The presence of a t(4;14) appears to confer an
extremely poor prognosis. Patients with this abnormality do not experience prolonged
remissions after a single autologous stem cell transplant (ASCT) using high-dose melphalan,
and the optimal therapy of this group has not yet been defined. Specifically, data from
Princess Margaret Hospital and the Mayo Clinic both indicate that the median
progression-free survival (PFS) is only about 8 months and overall survival 18-22 months
after ASCT. Unpublished data from the French IFM studies suggest that tandem transplants may
improve these results modestly, but the outcome is still inferior compared with other
cytogenetic subgroups.

Initial unpublished observations suggested that t(4;14) patients with relapsed/refractory
disease were uniquely sensitive to the new agent bortezomib. More recent information in
larger numbers of patients indicates that responses to single agent bortezomib are seen in
up to 50-65% of t(4;14) patients; the duration of response is similar to that seen in other
subsets, i.e. in the range of 5-7 months. Combinations of bortezomib with agents such as
doxorubicin, pegylated liposomal doxorubicin, thalidomide, cyclophosphamide, melphalan,
thalidomide and corticosteroids have been evaluated in a number of clinical studies in
recurrent myeloma, and the response rates (RR) appear to be improved compared to single
agent bortezomib, and toxicity has been acceptable.

In newly diagnosed myeloma patients, combinations such as VAD (vincristine, doxorubicin,
dexamethasone) and thalidomide + dexamethasone are often utilized before ASCT. A study by
Hussein et al. substituted pegylated liposomal doxorubicin for the conventional formulation
of doxorubicin and noted a similar response rate with less grade 3/4 neutropenia, alopecia
and sepsis; in addition, patients do not necessarily require a central venous catheter.
More recently, Cavenagh et al. has reported remarkable activity with the so-called PAD
regimen of bortezomib, doxorubicin and dexamethasone, with a combined CR + PR rate of 67%
following 1 cycle, and 93% after 4 cycles, with no impairment of the ability to collect
blood stem cells for ASCT. Preliminary data from an ongoing Canadian phase II study of
Doxil/Caelyx + Bortezomib + Dexamethasone (DBd), in which pegylated liposomal doxorubin,
bortezomib and dexamethasone are combined, has produced encouraging results to date with
minimal toxicity. In that study, DBd therapy was given for 4 cycles before ASCT
independently of cytogenetic classification.

Given the disappointing results with routine ASCT in t(4;14) patients, we propose this open
label phase II study of bortezomib along with dexamethasone and pegylated liposomal
doxorubicin (Doxil/Caelyx), referred to as the DBd regimen, for 4 cycles, followed by
post-induction therapy with cyclophosphamide + bortezomib + prednisone (referred to as the
CyBorP regimen) for 8 cycles. Since patients with t(4;14) remain at high risk for relapse,
maintenance therapy with dexamethasone weekly will be given until disease progression.
This approach will test the hypothesis that bortezomib-based therapy can improve the outcome
of newly diagnosed t(4;14) multiple myeloma patients.

C. OBJECTIVES OF THE STUDY: To evaluate the efficacy of the DBd regimen given as induction
therapy, followed by post-induction therapy with CyBorP and maintenance therapy with
dexamethasone in t(4;14) positive multiple myeloma (MM) patients.

Primary Objectives

- To determine the time to progression (TTP) with this treatment regimen. Secondary
Endpoints

- To determine the objective response rate following DBd induction therapy

- To determine the duration of response following DBd induction therapy

- To determine the objective response rate following CyBorP post-induction therapy

- To determine the duration of response following CyBorP post-induction therapy

- To determine PFS

- To determine overall survival

- To determine the safety profile of this regimen

- To examine the ability of bortezomib based regimens to repress FGFR3 signaling

D. STUDY DESIGN: This is an open-label, Phase II study of induction therapy with
bortezomib, pegylated liposomal doxorubicin (Doxil/Caelyx) and dexamethasone as initial
therapy in patients with t(4;14). Each 21 day-cycle consists of bortezomib 1.3 mg/m2 (given
as an I.V. bolus on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 to 21).
DOXIL/CAELYX 30 mg/m2 will be given after bortezomib as at least a 1-hour I.V. infusion on
Day 4 of each 21-day cycle. Dexamethasone 40 mg PO will be given on days 1-4, days 8-11 and
days 15-18 during the first cycle. For the subsequent 3 cycles, dexamethasone 40 mg PO will
be given on days 1-4 and days 11-14. Patients who do not experience disease progression may
undergo elective, as per the attending physician's discretion, stem cell mobilization
followed by stem cell collection and cryopreservation. Patients will then receive
post-induction therapy with cyclophosphamide + bortezomib + prednisone (1.5 mg/m2 bortezomib
on days 1, 8, and 15 I.V. + cyclophosphamide 300 mg/m2 PO weekly + prednisone 100 mg PO on
alternate days) for 8 monthly 28 day cycles, followed by maintenance therapy with 40 mg of
dexamethasone weekly per month until disease progression occurs.

E. PATIENT CHARACTERISTICS: Untreated multiple myeloma patients who are t(4;14) positive by
fluorescence in situ hybridization (FISH) will be considered for the study. Exclusion
criteria include inadequate liver function (aspartate aminotransferase {AST} and alanine
aminotransferase {ALT} > 2.5 times the upper limit of normal), thrombocytopenia (platelets <
50 X 109/L), neutropenia (absolute neutrophil count < 1.0 x 109/L), pregnant or lactating
women, and women of childbearing potential (WCBP) who are not using adequate contraception
and LVEF below the institutional LLN or less than 40%; whichever value is higher. A patient
may have received up to 4 months of other anti myeloma therapy, as part of the induction
therapy, prior enrollment and still be considered eligible to participate in the study, as
long as the patient's multiple myeloma has not progressed in the current regimen and the
other eligibility criteria are met.

F. STATISTICAL PLAN: The TTP from initiation of chemotherapy in patients treated with ASCT
for this subset is approximately 12 months. An increase in TTP from 12 to 21 months would be
of clinical significance. Using an 80% power to detect this time difference in a two-sided
comparison patient, a sample size of 36 evaluable patients is required. This calculation
assumes that each patient will be evaluated at a fixed time of 24 months. Assuming a 20%
drop-out rate, a total sample size of 45 patients will be required.

G. STUDY DESIGN: It is assumed that the new regimen will not be of further interest in
t(4;14) positive myeloma patients if the TTP from the time of starting induction therapy is
less than 21 months. Each patient will be followed every month until disease progression
and then after every 6 moths up to 5 years for survival. An interim analysis will also be
performed after 12 patients have completed the post-induction therapy with cyclophosphamide
+ bortezomib + prednisone (CyBorP).

H. PATIENT ACCRUAL AND STUDY DURATION: Patients with t(4;14) represents only 15% of all
myeloma patients, as such, accrual will be highly dependant on number of participating
centers. It is estimated that approximately 350 newly-diagnosed patients will require
cytogenetic screening in order to meet the accrual target. Accrual is expected to be
complete within 48 months. Additional time is required, of course, to allow the response
data to mature. All patients registered in the study will be accounted for (screen failures
+ enrolled patients). The number of patients who are not evaluable, who died or withdrew
before treatment began will be specified. The distribution of follow-up times will be
described and the number of patients lost to follow-up will be monitored.

I. EFFICACY PARAMETERS: Beginning in cycle 1, the response to treatment will be determined
during each cycle using the International Myeloma Working Group uniform response criteria
for multiple myeloma as outlined in Section 11.0. Responses will be assessed by monoclonal
protein, monoclonal paraprotein (M protein) quantification from serum and a 24-hour urine
collection (including immunofixation, if needed), bone marrow plasma cells, assessment of
lytic lesions, and soft tissue plasmacytomas. For patients with light chain disease or
non-secretory myeloma, a serum sample for FreeLiteTM testing will be obtained and the
results will be compared to the levels reported quantified in the urine.

J. REGISTRATION: Patients will be registered by completing the eligibility and enrollment
checklist and forwarding it by fax to the Multiple Myeloma Research Coordinator at Princess
Margaret Hospital at 416-946-4419, between the hours of 9 am and 4 pm EST, up to 5 business
days prior commencement of cycle 1 day 1. The research coordinator should also be contacted
by phone at 416 946-4627. The checklist will be verified and a patient number will be
assigned for eligible patients.

K. SAMPLE PROCESSING: Centralized screening will be employed at Princess Margaret Hospital.
Following informed consent site should send two fresh heparinized (green top tube) marrow
samples (5cc per tube or best available) by overnight courier (see Appendix VI for shipping
and notification instructions) for t4;14 screening test. Tri-color iFISH for t(4;14) will be
performed and reported back to referring site within 5-7 working days.