Carfilzomib, Pomalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by University of Chicago
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Chicago
ClinicalTrials.gov Identifier:
NCT01665794
First received: August 13, 2012
Last updated: October 14, 2014
Last verified: October 2014
  Purpose

This phase I/II trial studies the safety and the best dose of carfilzomib and to see how well it works when given together with pomalidomide and dexamethasone in treating patients with relapsed or refractory multiple myeloma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Pomalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving carfilzomib together with pomalidomide and dexamethasone may kill more cancer cells


Condition Intervention Phase
Multiple Myeloma
Drug: pomalidomide
Drug: carfilzomib
Drug: dexamethasone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Multicenter, Open-label, Single-arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment With Pomalidomide, Dexamethasone, and Carfilzomib (PdC) in Subjects With Relapsed and Relapsed/Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • MTD of carfilzomib when administered in combination with fixed dosing pomalidomide and dexamethasone [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Partial response rate after 4 courses according to IMW criteria [ Time Frame: 4 months ] [ Designated as safety issue: No ]
    The proportion and exact 95% binomial confidence interval for the response rate will be reported adjusted for the two-stage design of this trial.


Secondary Outcome Measures:
  • Overall response rate [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Defined as at least a partial response to therapy, will be reported along with its exact 95% binomial confidence

  • Time to progression [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Estimated using the product-limit method of Kaplan and Meier.

  • Duration of response [ Time Frame: From the date of the clinical examination which confirmed the response, until the date of disease progression, or censoring at the date of last clinical follow-up up to 2 years ] [ Designated as safety issue: No ]
    Assessed conditional upon achieving at least a partial response.

  • Progression-free survival [ Time Frame: From the date of first therapy until the date of documented disease progression or death up to 2 years ] [ Designated as safety issue: No ]
    Estimated using the product-limit method of Kaplan and Meier.

  • Overall survival [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Estimated using the product-limit method of Kaplan and Meier.


Estimated Enrollment: 92
Study Start Date: August 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carfilzomib, pomalidomide, dexamethasone)
Patients receive carfilzomib, pomalidomide, and dexamethasone at indicated doses and schedule every 28 days. Patients may continue to receive treatment in the absence of disease progression or unacceptable toxicity.
Drug: pomalidomide
Given PO
Other Name: CC-4047
Drug: carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171
Drug: dexamethasone
Given PO or IV
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) of carfilzomib when administered in combination with fixed dosing pomalidomide and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma.

II. To determine the efficacy of the combination regimen at the MTD as measured by partial response (PR) response rate defined as per International Myeloma Working Group (IMW) criteria.

SECONDARY OBJECTIVES:

I. To determine the best stringent complete response (sCR)/CR/nodular complete response (nCR) and >= very good partial response (VGPR) rates.

II. To estimate the time on study (TOS), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) distributions.

III. To further define the toxicity at the MTD.

TERTIARY OBJECTIVES:

I. To perform an analysis of a subset of patients who are refractory to either pomalidomide or carfilzomib or lenalidomide, bortezomib, and dexamethasone (RVD) combination.

II. To evaluate the status of minimal residual disease (MRD) in patient who achieve sCR, CR or nCR.

III. To evaluate prognostic markers and markers of response to pomalidomide, dexamethasone, and carfilzomib (PdC) in patients refractory to lenalidomide by analyzing pre-treatment clinical covariates and pre-treatment plasma cell profiles by proteomics and gene expression profiling (GEP).

OUTLINE: This is a phase I dose-escalation study of carfilzomib followed by phase II.

Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15 and 16, pomalidomide orally (PO) once daily (QD) on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Treatment repeats every 28 days for at least 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease may continue to receive treatment in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 3 months for up to 2 years.

  Eligibility

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

Inclusion Criteria:

  • Relapsed and relapsed/refractory multiple myeloma requiring systemic therapy
  • All patients must have failed 1+ prior treatment, one of which must include lenalidomide therapy and have been determined to be refractory to it

    • Refractory to lenalidomide will be defined as a history of progression on or within 60 days of completion of a regimen of a minimum of 2 cycles containing full or maximally tolerated dose of lenalidomide
    • Progressing on lenalidomide maintenance will be allowed provided that the trial of at least 2 months of lenalidomide at 25 mg or maximum tolerated dose was given to meet the lenalidomide refractory status
    • In addition to lenalidomide refractory, patients refractory to (1) pomalidomide (2) carfilzomib, or (3) RVD are permitted limited to separate cohorts enrollment
  • Measurable disease, as indicated by one or more of the following:

    • Serum M-protein >= 0.5 g/dL
    • Urine M-protein >= 200 mg/24 hours
    • If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable
  • Life expectancy of more than 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Bilirubin < 1.5 times the upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times ULN
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • Hemoglobin >= 8 g/dL
  • Platelet count >= 75 x 10^9/L; subjects may receive red blood cells (RBC) transfusions or platelet transfusions, if clinically indicated in accordance with institutional guidelines; however, screening platelet count should be independent of platelet transfusions for at least 2 weeks
  • Calculated or measured creatinine clearance of >= 30 mL/minute
  • Written informed consent in accordance with federal, local, and institutional guidelines
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25mIU/mL within 10-14 days and again within 24 hours prior to starting course 1 of 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 successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
  • Subjects must agree to adhere to all study requirements, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring

Exclusion Criteria:

  • Non-secretory or hyposecretory multiple myeloma, defined as < 0.5 g/dL M-protein in serum, < 200 mg/24 hr urine M-protein, or disease only measured by serum free light chain
  • Patients for whom there is the prospect of stem cell transplantation in the next 6 months in the treatment plan are excluded (including patients for whom the PdC regimen is being considered as pre-transplant cytoreduction)
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Plasma cell leukemia
  • Waldenström's macroglobulinemia or immunoglobulin M (IgM) myeloma
  • Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
  • Participation in an investigational therapeutic study within 3 weeks or within 5 drug half lives (t1/2) prior to first dose, whichever time is greater
  • Refractory to bortezomib, except if meeting criteria for RVD-refractory cohort
  • Pregnant or lactating females
  • History of allergy to mannitol or prior hypersensitivity to thalidomide, lenalidomide or pomalidomide
  • Major surgery within 3 weeks prior to first dose, prior peripheral stem cell transplant within 12 weeks of study enrollment, subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with the exception of hormones for thyroid conditions or estrogen replacement therapy [ERT], or any investigational therapy) within 21 days of enrollment
  • Myocardial infarction within 6 months prior to enrollment, New York Heart Associate (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • Uncontrolled hypertension or diabetes
  • Acute active infection requiring systemic antibiotics, antivirals, or anti fungals within two weeks prior to first dose
  • Known or suspected human immunodeficiency (HIV) infection, known HIV seropositivity
  • Active hepatitis A, B, or C infection
  • Non-hematologic malignancy within the past 3 years except adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix or breast, prostate cancer < Gleason grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
  • Any clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
  • Significant neuropathy (grades 3-4, or grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment
  • Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (eg, lansoprazole), enteric-coated aspirin, allopurinol or if a history of prior thrombotic disease, warfarin or low molecular weight heparin
  • Subjects in whom the required program of PO and IV fluid hydration is contraindicated, eg, due to pre-existing pulmonary, cardiac, or renal impairment
  • Subjects with known or suspected amyloidosis of any organ
  • Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01665794

Locations
United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637-1470
Contact: Andrzej J. Jakubowiak    773-834-1592    ajakubowiak@medicine.bsd.uchicago.edu   
Principal Investigator: Andrzej J. Jakubowiak         
United States, New Jersey
Hackensack University Medical Center Not yet recruiting
Hackensack, New Jersey, United States, 07601
Contact: David S. Siegel    201-336-8704    dsiegel@humed.com   
Principal Investigator: David S. Siegel         
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: Andrzej Jakubowiak University of Chicago Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT01665794     History of Changes
Other Study ID Numbers: 12-1088, NCI-2012-01168
Study First Received: August 13, 2012
Last Updated: October 14, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
BB 1101
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Pomalidomide
Thalidomide
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on October 22, 2014