Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma
Lenalidomide has clinical activity in myeloma. The closely related compound, Pomalidomide, may have clinical activity in patients who have previously been treated with lenalidomide and who no longer respond to it. The mechanism of anti-tumor effects of these drugs has been attributed to several effects including anti-angiogenesis, immune activation, and anti-proliferative effects. Recent studies have suggested that these agents can mediate surprisingly rapid biologic effects on human monocytes and T cells. Our hypothesis is that the proximate effects of these drugs 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 the pharmacodynamics of these effects with downstream activation using quantitative assays will facilitate the rational development of pomalidomide as immune-modulatory drug in diverse settings as well as its optimal development in myeloma therapy.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Clinical and Pharmacodynamic Comparison of Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma|
- To compare the clinical activity in terms of response rate following continuous or intermittent dosing regimens. [ Time Frame: Efficacy assessments will be made after the first two cycles of therapy (approximately 56 days--each cycle is 28 days) ] [ Designated as safety issue: No ]All partial and complete responses must be confirmed with another efficacy assessment in no less than 4 weeks apart.
- To compare the clinical activity in terms of response rate following continuous or intermittent dosing regimens. [ Time Frame: After the initial efficacy assessment at the completion of cycle 2 (at approximately 56 days), efficacy assessments will be made after every other cycle (approximately every 56 days). ] [ Designated as safety issue: No ]All partial and complete responses must be confirmed with another efficacy assessment in no less than 4 weeks apart.
- To compare the effect of continuous versus intermittent regimens on F actin polymerization in PBMC and activation of tumor antigen-specific T cells, as well as innate lymphocytes (NK or NKT cells). [ Time Frame: Research blood draw will be obtained at baseline, and at 2-4 hr (on day 1), 1 wk, and 4 wk after initiation of cycles 1 and 2. ] [ Designated as safety issue: No ]Correlation to be determined upon completion of study treatment
- To correlate drug induced biologic effects with adverse effects and clinical responses. [ Time Frame: Research bone marrow aspirate is obtained at baseline and after completion of 2 cycles of therapy (approximately 56 days) ] [ Designated as safety issue: Yes ]Research bone marrow aspirate is obtained to assess response (optional, but recommended), and to document complete remission, if applicable. Correlation to be determined upon completion of study treatment
- To correlate the drug induced proximate changes with effects on cytokine profile. [ Time Frame: Research blood draw will be obtained at baseline, and at 2-4 hr (on day 1), 1 wk, and 4 wk after initiation of cycles 1 and 2. ] [ Designated as safety issue: No ]Correlation to be determined upon completion of study treatment
|Study Start Date:||June 2011|
|Estimated Study Completion Date:||December 2014|
|Estimated Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
|Experimental: Pomalidomide 2 mg/d days 1-28 of a 28 day cycle||
Comparison of different dosages and schedules of drug
Other Name: CC-4047
|Experimental: Pomalidomide 4 mg/d days 1-21 of a 28 day cycle||
Comparison of different dosages and schedules of drug
Other Name: CC-4047
Hide Detailed Description
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01319422
|United States, Connecticut|
|New Haven, Connecticut, United States, 06520|
|Principal Investigator:||Madhav Dhodapkar, M.D.||Yale University|