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

This study is currently recruiting participants.
Verified July 2011 by Yale University
Sponsor:
Collaborator:
Celgene Corporation
Information provided by:
Yale University
ClinicalTrials.gov Identifier:
NCT01319422
First received: March 14, 2011
Last updated: July 5, 2011
Last verified: July 2011
  Purpose

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.


Condition Intervention Phase
Multiple Myeloma
Drug: Pomalidomide
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 48
Study Start Date: June 2011
Estimated Study Completion Date: November 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pomalidomide 2 mg/d days 1-28 of a 28 day cycle Drug: Pomalidomide
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 Drug: Pomalidomide
Comparison of different dosages and schedules of drug
Other Name: CC-4047

  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01319422

Contacts
Contact: Madhav Dhodapkar, M.D. 203-785-4144 madhav.dhodapkar@yale.edu

Locations
United States, Connecticut
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Madhav Dhodapkar, M.D.    203-785-4144    madhav.dhodapkar@yale.edu   
Sub-Investigator: Dennis Cooper, M.D.         
Sub-Investigator: Francine Foss, M.D.         
Sub-Investigator: Peter Marks, M.D.         
Sub-Investigator: Stuart Seropian, M.D.         
Sub-Investigator: Nikolai Podolstev, M.D., Ph.D.         
Sponsors and Collaborators
Yale University
Celgene Corporation
Investigators
Principal Investigator: Madhav Dhodapkar, M.D. Yale University
  More Information

No publications provided

Responsible Party: Madhav Dhodapkar, M.D., Yale University
ClinicalTrials.gov Identifier: NCT01319422     History of Changes
Other Study ID Numbers: HIC 1011007607
Study First Received: March 14, 2011
Last Updated: July 5, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Yale University:
myeloma
multiple myeloma
pomalidomide
immunomodulatory

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Thalidomide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on April 21, 2014