Clinical and Pharmacodynamic Comparison of 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
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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To compare the clinical activity in terms of response rate following continuous or intermittent dosing regimens.
All partial and complete responses must be confirmed with another efficacy assessment in no less than 4 weeks apart.
Efficacy assessments will be made after the first two cycles of therapy (approximately 56 days--each cycle is 28 days)
Madhav Dhodapkar, M.D.
United States: Food and Drug Administration
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