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Carfilzomib and Dexamethasone for Treating Patients With Relapsed or Refractory Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2015 by Southwest Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Southwest Oncology Group
ClinicalTrials.gov Identifier:
NCT01903811
First received: July 16, 2013
Last updated: August 18, 2015
Last verified: August 2015
  Purpose

This randomized phase II trial compares how well two different doses of carfilzomib work when given with dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement or has not responded to treatment. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving carfilzomib together with dexamethasone may kill more cancer cells. It is not yet known whether a higher or lower dose of carfilzomib works better when given with dexamethasone.


Condition Intervention Phase
Recurrent Plasma Cell Myeloma
Refractory Plasma Cell Myeloma
Drug: Carfilzomib
Drug: Dexamethasone
Other: Laboratory Biomarker Analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Randomized Study Comparing Two Doses of Carfilzomib (NSC-756640) With Dexamethasone for Multiple Myeloma Patients With Relapsed or Refractory Disease

Resource links provided by NLM:


Further study details as provided by Southwest Oncology Group:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 2 years ] [ Designated as safety issue: No ]
    Assessed in each arm using the method of Kaplan Meier and compared between arms using the stratified long-rank test.


Secondary Outcome Measures:
  • Overall survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Assessed in each arm using the method of Kaplan Meier and compared between arms using the stratified log-rank test.

  • Response rate (stringent complete response [sCR], complete response [CR], very good partial response [VGPR], partial response [PR]) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Assessed in each arm and compared between arms using Fisher's exact test.


Other Outcome Measures:
  • Gene expression profiles [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Bone marrow compared to that of an aspirate taken at the site of the EMP. Data will be log-transformed before analysis. Exploratory analyses will examine underlying distributions using boxplots, density plots, scatter plots, etc. For differential expression analysis of the two sample types t-tests will be conducted on genes. False discovery rate will be used to control the average false positive proportions among selected genes. Genes will be ranked by their q-value and pathway analysis conducted upon selected genes to determine biological plausibility and relevance to molecular functionality.

  • Incidence of CR by PET, defined as the disappearance of all focal lesions and the resolution of EMD [ Time Frame: Up to week 45 ] [ Designated as safety issue: No ]
    Univariate and multivariate logistic regression will be used to determine the impact of biochemical CR on CR by PET. In the multivariate analysis adjustment for standard prognostic factors such as age, albumin, beta-2 microglobulin, serum creatinine, c-reactive protein and lactate dehydrogenase will be included.


Estimated Enrollment: 140
Study Start Date: October 2013
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (dexamethasone, low-dose carfilzomib)
Patients receive dexamethasone IV and low-dose carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients with progression cross-over to Arm II.
Drug: Carfilzomib
Given IV
Other Names:
  • CARFILZOMIB
  • Kyprolis
  • PR-171
Drug: Dexamethasone
Given IV
Other Names:
  • Aacidexam
  • Adexone
  • Aknichthol Dexa
  • Alba-Dex
  • Alin
  • Alin Depot
  • Alin Oftalmico
  • Amplidermis
  • Anemul mono
  • Auricularum
  • Auxiloson
  • Baycuten
  • Baycuten N
  • Cortidexason
  • Cortisumman
  • Decacort
  • Decadrol
  • Decadron
  • Decalix
  • Decameth
  • Decasone R.p.
  • Dectancyl
  • Dekacort
  • Deltafluorene
  • Deronil
  • Desamethasone
  • Desameton
  • Dexa-Mamallet
  • Dexa-Rhinosan
  • Dexa-Scheroson
  • Dexa-sine
  • Dexacortal
  • Dexacortin
  • Dexafarma
  • Dexafluorene
  • Dexalocal
  • Dexamecortin
  • Dexameth
  • DEXAMETHASONE
  • Dexamethasonum
  • Dexamonozon
  • Dexapos
  • Dexinoral
  • Dexone
  • Dinormon
  • Fluorodelta
  • Fortecortin
  • Gammacorten
  • Hexadecadrol
  • Hexadrol
  • Lokalison-F
  • Loverine
  • Methylfluorprednisolone
  • Millicorten
  • Mymethasone
  • Orgadrone
  • Spersadex
  • Visumetazone
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm II (dexamethasone, high-dose carfilzomib)
Patients receive dexamethasone IV and high-dose carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: Carfilzomib
Given IV
Other Names:
  • CARFILZOMIB
  • Kyprolis
  • PR-171
Drug: Dexamethasone
Given IV
Other Names:
  • Aacidexam
  • Adexone
  • Aknichthol Dexa
  • Alba-Dex
  • Alin
  • Alin Depot
  • Alin Oftalmico
  • Amplidermis
  • Anemul mono
  • Auricularum
  • Auxiloson
  • Baycuten
  • Baycuten N
  • Cortidexason
  • Cortisumman
  • Decacort
  • Decadrol
  • Decadron
  • Decalix
  • Decameth
  • Decasone R.p.
  • Dectancyl
  • Dekacort
  • Deltafluorene
  • Deronil
  • Desamethasone
  • Desameton
  • Dexa-Mamallet
  • Dexa-Rhinosan
  • Dexa-Scheroson
  • Dexa-sine
  • Dexacortal
  • Dexacortin
  • Dexafarma
  • Dexafluorene
  • Dexalocal
  • Dexamecortin
  • Dexameth
  • DEXAMETHASONE
  • Dexamethasonum
  • Dexamonozon
  • Dexapos
  • Dexinoral
  • Dexone
  • Dinormon
  • Fluorodelta
  • Fortecortin
  • Gammacorten
  • Hexadecadrol
  • Hexadrol
  • Lokalison-F
  • Loverine
  • Methylfluorprednisolone
  • Millicorten
  • Mymethasone
  • Orgadrone
  • Spersadex
  • Visumetazone
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate and compare progression free survival (PFS) of two different doses of carfilzomib with dexamethasone in multiple myeloma (MM) patients with relapsed and/or refractory disease.

SECONDARY OBJECTIVES:

I. To evaluate and compare response rates (RR) for each arm. II. To evaluate response rates (RR) for patients that relapse on low dose carfilzomib and subsequently cross-over to high dose carfilzomib.

III. To evaluate the safety of this combination for this patient population. IV. To evaluate overall survival (OS).

TERTIARY OBJECTIVES:

I. To explore the molecular variability in MM cells obtained from extramedullary bone marrow relapse sites.

II. To explore the role of positron emission tomography (PET) scanning in assessing disease burden and as a tool to assess treatment response.

III. To explore changes in left ventricular ejection fraction (LVEF) in patients with relapsed or refractory multiple myeloma treated with low dose carfilzomib or high dose carfilzomib plus dexamethasone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive dexamethasone intravenously (IV) and low-dose carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16. Patients with progression cross-over to Arm II.

ARM II: Patients receive dexamethasone IV and high-dose carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16.

Note that for the first course of treatment on both arms carfilzomib is given at a reduced rate to assess toxicity.

In both arms, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years from initial registration.

  Eligibility

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

Inclusion Criteria:

  • REGISTRATION STEP 1: INITIAL RANDOMIZATION
  • Patients must have a confirmed diagnosis of symptomatic multiple myeloma and must be currently relapsed or refractory; all tests for establishing disease status must be completed within 28 days prior to registration and documented on the Baseline Tumor Assessment Form for Multiple Myeloma
  • Patients must have measurable disease within 28 days prior to registration
  • Patients must have received at least one prior regimen of chemotherapy for symptomatic multiple myeloma; patients may not have more than six (6) previous regimens of therapy for the disease; prior chemotherapy must have been completed at least 21 days prior to registration; for study purposes, a regimen is defined as follows:

    • An anti-myeloma therapy used at the time of initial diagnosis or documented disease progression which is given with the intent to decrease disease burden
    • Any maintenance therapy used after an Induction should be considered part of that Induction regimen
    • Use of any agent or combination of agents more than once during the patient's disease history for separate documented disease progressions will be counted as separate regimens (e.g., if a patient receives lenalidomide/bortezomib at initial diagnosis and achieves response, but then progresses and receives lenalidomide/bortezomib after progression, these count as 2 separate regimens)
    • In cases of allogeneic or autologous stem cell transplant, the entire induction + stem cell mobilization + conditioning + planned maintenance should be considered one regimen
  • Patients may not have received any prior carfilzomib treatment
  • Patients must not be receiving any other concurrent therapy considered to be investigational; patients must not be planning to receive any radiotherapy (except localized radiation for palliative care); patients must not be planning to receive any concurrent chemotherapy, immunotherapy, radiotherapy or other treatment with curative intent
  • Patients must have complete history and physical examination within 28 days prior to registration
  • Patients must have baseline PET scan within 28 days prior to registration; note that images are submitted centrally for review
  • Patients with non-secretory MM or known primary amyloidosis are not eligible
  • Patients must have Zubrod performance status 0-2
  • Patients must not have clinically significant illness including uncontrolled, active infection requiring intravenous antibiotics, New York Heart Association (NYHA) class III or class IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or >= grade 3 cardiac arrhythmias
  • Patients must have undergone an electrocardiogram (EKG) within 28 days prior to registration
  • Patients must have either echocardiogram (ECHO) with ejection fraction >= 45% within 28 days prior to registration
  • Patients must not have > grade 2 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN
  • Absolute neutrophil count (ANC) >= 1,000 cell/mm^3 without growth factor support within 14 days prior to registration
  • Platelets >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis < 50% or >= 30,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50% within 14 days prior to registration
  • Calculated or measured creatinine clearance >= 30 ml/min within 14 days prior to registration
  • Patients who are known to be human immunodeficiency virus positive (HIV+) are eligible providing they meet all of the following additional criteria within 28 days prior to registration:

    • Cluster of differentiation (CD)4 cells >= 500/mm^3
    • Viral load of < 50 copies HIV messenger ribonucleic acid (mRNA)/mm^3 if on combination antiretroviral therapy (cART) or < 25,000 copies HIV mRNA if not on cART
    • No zidovudine or stavudine as part of cART
    • Patients who are HIV+ and do not meet all of these criteria are not eligible for this study
  • Patients with known hepatitis B or hepatitis C infection must have viral load < 800,000 IU/L within 28 days prior to registration
  • Patients must have baseline skeletal survey to document lytic lesions, osteopenia or compression fracture within 28 days prior to registration
  • Patients may have received palliative external beam radiation therapy (XRT) for local disease control with no curative intent. XRT must be completed at least 7 days prior to registration
  • Patients must be offered participation in specimen submission for translational medicine studies and banking; with patient consent, specimens must be submitted
  • Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years
  • Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
  • REGISTRATION STEP 2: CROSSOVER
  • Patient must have been eligible for and initially randomized to Arm 1 (low dose carfilzomib), begun cycle 2 of treatment, and progressed prior to completing 12 cycles of protocol therapy
  • At least 14 days and no more than 28 days must have elapsed between the last day of treatment on Arm 1 and registration to Arm 3
  • Patients must have recovered from all non-hematologic toxicities to =< grade 2 and from all hematologic toxicities to =< grade 3 prior to registration
  • Patients must have begun cycle 2 (carfilzomib - 27 mg/m^2) and must not have received any dose reduction for toxicity in the last cycle of treatment, immediately preceding progression
  • Patients must have serum protein electrophoresis (SPEP) and kappa and lambda light chain testing performed within 14 days prior to registration in order to establish baseline measurements
  • Patients must not have ejection fraction decrease > 10% from baseline (as determined by ECHO) or other ejection fraction decrease accompanied by other clinical signs/symptoms of New York Heart Association (NYHA) class III or IV heart failure, measured within 28 days prior to registration; if any question exists regarding individual patient eligibility in this situation, contact the study chair for determination
  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: NCT01903811

Contacts
Contact: Cara Laubach, MIIM 210/614-8808 claubach@swog.org
Contact: Dana Sparks, MAT 210/614-8808 dsparks@swog.org

  Show 459 Study Locations
Sponsors and Collaborators
Southwest Oncology Group
Investigators
Principal Investigator: Sikander Ailawadhi Southwest Oncology Group
  More Information

No publications provided

Responsible Party: Southwest Oncology Group
ClinicalTrials.gov Identifier: NCT01903811     History of Changes
Other Study ID Numbers: S1304, NCI-2013-00796, PS1304_A07PAMDREVW01, SWOG-S1304, S1304, S1304, U10CA180888, U10CA032102
Study First Received: July 16, 2013
Last Updated: August 18, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Southwest Oncology Group:
carfilzomib
relapsed
refractory
multiple myeloma

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
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 01, 2015