A PHASE 2 MULTICENTER, OPEN-LABEL STUDY TO DETERMINE THE EFFICACY AND SAFETY OF POMALIDOMIDE (CC-4047) IN COMBINATION WITH LOW-DOSE DEXAMETHASONE IN SUBJECTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA AND MODERATE OR SEVERE RENAL IMPAIRMENT INCLUDING SUBJECTS UNDERGOING HEMODIALYSIS

Multiple myeloma (MM) is an incurable disease that is characterized by the
accumulation of clonal plasma cells in the bone marrow (Alexanian, 1994) and
accounts for 10% of all hematological malignancies. In 2011, it was estimated
that 20,520 new cases of MM and 10,610 deaths from the disease would occur in
the United States (US) (Siegel, 2011). In Europe, there are approximately
27,800 new cases each year (Boyle, 2005). The disease follows a relapsing
course in the majority of patients, regardless of treatment regimen or initial
response to treatment. While MM patients with relapsed and/or refractory
disease may achieve responses to subsequent antimyeloma therapies, the duration
of response typically decreases with successive relapses (Kumar, 2004) until
resistant disease develops reflecting changes in disease biology,
with more tumor cells expressing a more aggressive phenotype, higher
proliferative thrust, and lower apoptotic rates (Anderson, 2008).

Pomalidomide in combination with low-dose dexamethasone has shown activity in
several Phase 1, Phase 2, and recently in a Phase 3 trial. The dose of 4 mg was
established in a Phase 1 trial (CC-4047-MM-002; NCT00833833) which also
achieved 42% minimal response or better, 21% partial response or better and 3%
complete response in a heavily pretreated population (Richardson, 2012). In a
Phase 2 trial following this Phase 1, response rates of a partial response (PR)
of at least 31.3% could be achieved as well as a median progression-free
survival of 3.8 months (Richardson, 2011). A Phase 2 trial conducted by the
Intergroupe Francophone du Myelome (IFM) confirmed high efficacy of the
combination of pomalidomide and dexamethasone in subjects refractory to
bortezomib and lenalidomide with response rates of 35% (Leleu, 2013). Recently,
results of a Phase 3 trial comparing pomalidomide plus low-dose dexamethasone
to high dose dexamethasone in heavily pretreated patients have shown
significant improvement in progression free survival as well as overall
survival (Dimopoulos, 2012).
However, only few subjects with renal insufficiency were evaluated so far, as
inclusion criteria of most trials did not allow inclusion of subjects suffering
from renal insufficiency having a creatinine clearance < 45 mL/min. Very
preliminary data suggest that subjects with renal insufficiency will benefit
from treatment with pomalidomide and low-dose dexamethasone. A Phase 1 trial is
currently ongoing to define the maximum tolerated dose of pomalidomide in
combination with low-dose dexamethasone in subjects with RRMM and impaired
renal function.
However, as pomalidomide is highly metabolized and as only 5% of doses are
unchanged in urine, it is hypothesized that renal impairment will not affect
exposure to pomalidomide in a clinically relevant manner. This trial will
further investigate the activity of the combination of pomalidomide and
low-dose dexamethasone in subjects with renal insufficiency. In order to be
able to better distinguish between different grades of renal insufficiency
three different cohorts were chosen dependent on the grade of renal impairment.
Very preliminary data suggest that adverse events occurring in subjects with
renal impairment might not be different from adverse events occurring in
subjects with normal renal function when being treated with pomalidomide and
low dose dexamethasone (Siegel, 2012). Looking at three different cohorts will
give specific information about response rates as well as renal response rates
dependent on the eGFR at the time of inclusion into this trial.
Cohort A will include subjects with an estimated Glomerular Filtration Rate of
30 < eGFR < 45 mL/min/1.73 m2. It was chosen to limit the upper level to 45
mL/min/m2 according to the available data from other trials, as subjects having
an eGFR of more than 45 mL/min/1.73 m2 were already included into other trials.
Subjects who show renal insufficiency with an eGFR of < 30 mL/min/1.73 m2 will
be included into Cohort B, as long as they do not need to undergo dialysis;
cohort C will include subjects on dialysis.
Subjects may be enrolled either if developing acute renal insufficiency or
showing chronic renal insufficiency over a longer period. For subjects who
develop acute renal insufficiency the deterioration over time will be evaluated
and recorded. Treatment Duration Treatment will be given until disease
progression, as other studies investigating pomalidomide in combination with
low-dose dexamethasone have proven to show benefit for subjects if they are on
continuous treatment.
All three cohorts will enroll in parallel; subjects will remain in their
assigned cohorts even when renal function might improve or deteriorate during
the study. Subjects will be discontinued at time of disease progression or in
the case of intolerable toxicity. All subjects will be followed for survival,
subsequent antimyeloma therapies, and second primary malignancies.

Primary Objective:
- Evaluate efficacy of the combination of pomalidomide and low-dose
dexamethasone in subjects with relapsed or refractory multiple myeloma and
impaired renal function.

Secondary Objectives:
- Evaluate renal efficacy of the combination of pomalidomide and low-dose
dexamethasone in subjects with various degrees of renal impairment.
- Evaluate safety and tolerability of the combination of pomalidomide and
low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma
and impaired renal function.
- Evaluate the pharmacokinetics of pomalidomide in subjects with various
degrees of renal impairment.

This is an international Phase 2 multicenter open-label study of pomalidomide
in combination with low-dose dexamethasone in subjects with relapsed or
refractory multiple myeloma and impaired renal function requiring or not
requiring hemodialysis.
This study will include three cohorts (Cohorts A, B, and C)
- Cohort A will be relapsed or refractory multiple myeloma subjects with
moderate renal impairment (30 < estimated glomerular filtration rate (eGFR) <
45 mL/min/1.73 m2)
- Cohort B will be relapsed or refractory multiple myeloma subjects with severe
renal impairment not requiring hemodialysis (eGFR < 30 mL/min/1.73 m2)
- Cohort C will be relapsed or refractory multiple myeloma subjects with severe
renal impairment requiring hemodialysis

This study consists of the following consecutive phases: Screening, Treatment,
and Follow-up.:

Screening Phase
Potential study subjects will sign an informed consent document (ICD) prior to
undergoing any study-related procedure. Subjects will undergo screening for
protocol eligibility within 28 days prior to Cycle 1 Day 1.
Subjects in Cohorts A and B may participate in an exploratory biomarker
substudy conducted at selected clinical sites able to perform the required
collection and processing of samples.

Treatment Phase
Study treatment administration should start within 72 hours after enrollment of
the subject into the study, provided that the inclusion/exclusion criteria are
still met. Each subject will receive the following study treatment until
progressive disease (PD) or study discontinuation due to other
reasons:
- Pomalidomide administered orally at the starting dose of 4 mg on Days 1to 21
of a 28-day cycle
- Low-dose dexamethasone administered orally at the starting dose of 40 mg/day
(* 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of a
28-day cycle
All three cohorts will enroll in parallel; all cohorts will receive the same
study treatment, subjects who are included in Cohort C should receive IP after
hemodialysis on non-PK dialysis days. Subjects may not be enrolled in more than
1 cohort. The study will be conducted in Europe.

Follow-up Phase
All study subjects will enter the follow-up phase within 28 days of last study
treatment administration. During long-term follow-up the following information
will be collected from all subjects every 3 months for up to 5 years after last
subject enrollment or longer if clinically indicated: SPM, survival and all
subsequent antimyeloma treatment (type of treatment, start and stop dates, best
response) as well as date of progression based on the updated IMWG uniform
response criteria at each change of treatment line.

All subjects will receive oral doses of pomalidomide, at a starting dose of 4
mg on Days 1to 21 of a 28-day cycle and low-dose dexamethasone administered
orally at a starting dose of 40 mg/day in subjects * 75 years and 20 mg in
subjects aged over 75 years on Days 1, 8, 15, and 22 of the 28-day cycle. All
subjects will continue study treatment until disease progression or
unacceptable toxicity leading to treatment discontinuation. All subjects will
be followed up for survival, serious adverse events (specifically including
second primary malignancy) and subsequent antimyeloma therapies within 28 days
of the last study treatment. Thereafter, every 3 months for a period of 5 years
after last subject enrollment (or longer if clinically warranted), survival,
subsequent anti-myeloma therapies and SPM will be collected during
Follow-up-phase.

See section E9.