Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma

Multiple Myeloma (MM) is a common hematologic malignancy characterized by clonal expansion
of transformed plasma cells (PCs) in the bone marrow1. Over the past decade, the
introduction of immunomodulatory agents (such as thalidomide and lenalidomide) and
proteasome inhibitors (such as bortezomib) as effective therapies has altered the
therapeutic landscape for multiple myeloma (MM). Following the approval and establishment of
thalidomide-containing regimens, such as melphalan, prednisone and thalidomide (MPT) and
Thal/Dex, as the standard first-line therapy for newly diagnosed MM (NDMM), lenalidomide in
combination with dexamethasone (RD) was approved for the treatment of patients with
previously treated MM1. However, even with these newly approved agents, MM remains an
incurable disease and most patients will eventually relapse and progress after multiple
lines of different therapeutic regimens including both lenalidomide as well as bortezomib.
Thus there remains a continued need to identify newer agents to maintain long term disease
control in these patients.

Thalidomide and its immune-modulatory analogue lenalidomide have clinical activity in
myeloma. Pomalidomide, a thalidomide analogue, is an immunomodulatory agent that displays
similar anti-angiogenic activity, but far greater anti-proliferative and immunomodulatory
activity, compared to the parent drug. Pomalidomide and lenalidomide have been shown to
possess very similar pharmacological properties in vitro, including anti-angiogenic,
immunomodulatory and anti-proliferative properties. However a unifying molecular mechanism
for these diverse effects has been elusive. Pomalidomide and lenalidomide have significantly
greater capacity for enhanced costimulation, leading to enhanced activation of innate and
adaptive immune cells compared to Thalidomide. Recent studies have yielded the surprising
finding that these agents can mediate rapid biologic effects on human monocytes and T cells
in culture leading to activation of RhoA GTPases, and enhanced actin polymerization. Changes
in actin cytoskeleton may also contribute to the capacity to these drugs to enhance the
formation of immune synapses, Pomalidomide has also been shown to stimulate
antibody-dependent cytotoxic T-cell activity (ADCC) in preclinical models.

At tolerated doses (MTD = 2 mg QD and 5 mg QOD), pomalidomide has been shown to be active in
subjects with relapsed or refractory multiple myeloma (MM) (study CC-4047-00-001). In 45
subjects who received doses of pomalidomide ranging, by cohort, up to 10 mg daily, the most
commonly occurring dose-limiting toxicity (DLT) was reversible neutropenia. As with other
IMiDs administered to subjects receiving concomitant systemic steroids, deep vein thrombosis
(DVT) was seen (in 1 subject each in this study and in its subsequent named patient supply
rollover program).

Recently, preliminary efficacy and safety data from an ongoing phase II study, led by Martha
Lacy at Mayo Clinic, were published. Sixty patients with relapsed or refractory multiple
myeloma were enrolled. Pomalidomide (CC-4047) was given orally at a dose of 2 mg daily on
days 1-28 of a 28-day cycle and dexamethasone was given orally at a dose of 40 mg daily on
days 1, 8, 15, 22 of each cycle. Patient also received aspirin 325 mg once daily for
thromboprophylaxis. The study endpoints were the response rate in patients taking
pomalidomide plus dexamethasone including patients with lenalidomide resistant refractory
multiple myeloma, and safety of pomalidomide plus dexamethasone. Responses were recorded
using the criteria of the International Myeloma Working Group. Thirty eight patients
achieved objective response (63%) including CR in 3 patients (5%), VGPR in 17 patients
(28%), and PR in 18 patients (30%). The CR + VGPR rate was 33%. Grade 3 or 4 hematologic
toxicity occurred in 23 patients (38%) and consisted of anemia in three patients (5%),
thrombocytopenia in two patients (3%) and neutropenia in 21 (35%). Among those that
developed grade 3/4 neutropenia, all first experienced the neutropenia in cycle 1-3; no new
patients experienced grade 3/4 neutropenia in cycle 4 or later. The most common
non-hematological grade 3/4 toxicities were fatigue (17%) and pneumonia (8%). Other grade
3/4 non-hematological toxicities that occurred in less than 5% included diarrhea,
constipation, hyperglycemia, and neuropathy. One patient (1.6%) had a thromboembolic event
of deep vein thrombosis.

Another dosing regimen for Pomalidomide involved 21/28 day dosing, as in the current dosing
regimen for Lenalidomide. In this trial the recommended dose for phase II testing was
determined to be 4 mg, 21/28 d. Clinical response (greater than or equal to a partial
response (PR)) was observed in 7/25 (28%) patients. While both regimens seem to be
clinically active, it is unclear at present as to which regimen leads to greater immune
activation or clinical activity.

In addition to MM, pre-clinical data and the prior experience with thalidomide and
lenalidomide in the treatment of patients with myelofibrosis with myeloid metaplasia (MMM)
provided the rationale for the use of pomalidomide in patients with MMM. This is further
supported by the results of a Celgene sponsored trial (MMM-001) which indicated that
pomalidomide therapy at 0.5 mg or 2 mg/day +/- an abbreviated course of prednisone is well
tolerated in patients with myelofibrosis and active in the treatment of anemia.

However, these studies did not monitor proximate pharmacodynamic events (such as might occur
within hours of drug exposure), and link these to downstream effects, including clinical
activity and toxicity. Our hypothesis is that the proximate effects of these drugs
(including drug induced changes in F-actin) and early phosphorylation events will be
sensitive and quantitative surrogates of subsequent effects including activation of tumor
antigen specific T cells as well as innate immune cells. Understanding the correlation
between pharmacodynamics of these effects with downstream activation using quantitative
assays will facilitate rational development of these agents as immunomodulatory drugs in
diverse settings and may also allow optimization of drug delivery to both reduce potential
toxicity, and enhance efficacy.

Inclusion Criteria:

- Understand and voluntarily sign an informed consent form.

- Age ≥18 years at the time of signing the informed consent form.

- Able to adhere to the study visit schedule and other protocol requirements.

- Relapsed / Refractory Multiple Myeloma following at least two prior standard
therapies including lenalidomide. Induction therapy followed by autologous stem cell
transplantation (ASCT) is considered one regimen.

- Patients must be refractory to prior lenalidomide therapy. For the purpose of this
protocol, refractory will be defined as history of progression on a regimen
containing full or maximally tolerated dose of lenalidomide administered for a
minimum of at least one complete cycle of therapy.

- All patients must have measurable disease defined as one or more of the following
criteria:

- Serum monoclonal protein greater than 10 g/L, serum immunoglobulin free light
chain (FLC) more than 10 mg/dL and an abnormal FLC ratio, urine light-chain
excretion > 200 mg/24 h, measurable soft tissue plasmacytoma that has not been
irradiated, or greater than 30% plasma cells in bone marrow.

- All previous cancer therapy, including radiation, hormonal therapy and surgery, must
have been discontinued at least 2 weeks prior to treatment in this study.

- ECOG performance status of ≤ 2 at study entry (see Appendix D).

- Laboratory test results within these ranges:

- Absolute neutrophil count ≥ 1.0 x 1000/uL

- Platelet count ≥ 75 x 1000/uL

- Serum creatinine ≤ 2.5 mg/dL

- Total bilirubin ≤ 2 mg/dL

- AST (SGOT) and ALT (SGPT) ≤ 5 x ULN

- Disease free of prior malignancies for ≥ 5 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix
or breast.

- Females of childbearing potential (FCBP)† must have a negative serum or urine
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to
and again within 24 hours of starting pomalidomide and must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also
agree to ongoing pregnancy testing. Men must agree to use a latex condom during
sexual contact with a FCBP even if they have had a vasectomy. All patients must be
counseled at a minimum of every 28 days about pregnancy precautions and risks of
fetal exposure. See Appendix A and B: Risks of Fetal Exposure, Pregnancy Testing
Guidelines and Acceptable Birth Control Methods, AND also Education and Counseling
Guidance Document.

- Able to take aspirin (81 mg) daily as prophylactic anticoagulation (patients
intolerant to ASA may use warfarin or low molecular weight heparin).

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form.

- Pregnant or breast feeding females. (Lactating females must agree not to breast feed
while taking pomalidomide).

- Women of child-bearing potential who are unwilling to use a dual method of
contraception; and men who are unwilling to use a condom.

- Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

- Use of any other experimental drug or therapy within 28 days of baseline.

- Known hypersensitivity to thalidomide or lenalidomide.

- The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide, pomalidomide or similar drugs.

- Any prior use of pomalidomide.

- Concurrent use of other anti-cancer agents or treatments.

- Known positive for HIV or active infectious hepatitis, B or C.

- Grade 3 or 4 peripheral neuropathy