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Selinexor, Carfilzomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma (SINE)

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ClinicalTrials.gov Identifier: NCT02199665
Recruitment Status : Recruiting
First Posted : July 24, 2014
Last Update Posted : April 11, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Chicago

Tracking Information
First Submitted Date  ICMJE July 22, 2014
First Posted Date  ICMJE July 24, 2014
Last Update Posted Date April 11, 2018
Actual Study Start Date  ICMJE June 12, 2014
Estimated Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
Maximum Tolerated Dose (MTD) of selinexor, carfilzomib, and dexamethasone [ Time Frame: 28 days ]
Defined as the dose level below the dose in which greater than or equal to 2 out of 6 patients experience dose limiting toxicity. Will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Original Primary Outcome Measures  ICMJE
 (submitted: July 22, 2014)
MTD and RP2D selinexor, carfilzomib, and dexamethasone defined as the dose level below the dose in which greater than or equal to 2 out of 6 patients experience dose limiting toxicity [ Time Frame: 28 days ]
Will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Change History Complete list of historical versions of study NCT02199665 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2014)
  • Incidence of toxicities related to the combination of selinexor and carfilzomib assessed using NCI CTCAE version 4.0 [ Time Frame: Up to 28 days after completion of study treatment ]
  • Efficacy as measured by stable disease or better (including MR, partial response, very good partial response, complete response and stringent complete response) according to IMWG criteria [ Time Frame: Up to 2 years ]
    The number of patients with stable disease or better will be summarized by dose level; 90% confidence intervals will be generated for the RP2D cohort.
  • Incidence of toxicities assessed using NCI CTCAE version 4.0 [ Time Frame: Up to 28 days after completion of study treatment ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: July 22, 2014)
Changes in biomarkers [ Time Frame: Baseline to up to 2 years ]
Changes in biomarkers pre-post therapy will be summarized by dose level (mean, standard deviation) and analyzed in the RP2D cohort using paired t-tests.
 
Descriptive Information
Brief Title  ICMJE Selinexor, Carfilzomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma
Official Title  ICMJE A Phase I Study of the Combination of a Selective Inhibitor of Nuclear Export (SINE), Selinexor With Carfilzomib and Dexamethasone in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma
Brief Summary This phase I trial studies the side effects and best dose of selinexor and carfilzomib when given together with dexamethasone in treating patients with multiple myeloma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as selinexor and 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. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving selinexor, carfilzomib, and dexamethasone may be a better treatment for multiple myeloma.
Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the combination of selinexor, carfilzomib, and dexamethasone in relapsed and relapsed/refractory multiple myeloma.

SECONDARY OBJECTIVES:

I. Determine safety and tolerability.

II. Determine the efficacy, as measured by the rates of stable disease or better (including minimal response, partial response, very good partial response, complete response, and stringent complete response).

OUTLINE: This is a dose-escalation study of selinexor and carfilzomib.

Patients receive selinexor orally (PO), carfilzomib intravenously (IV), and dexamethasone PO QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Refractory Multiple Myeloma
Intervention  ICMJE
  • Drug: selinexor
    Given PO
    Other Names:
    • CRM1 nuclear export inhibitor KPT-330
    • KPT-330
    • selective inhibitor of nuclear export KPT-330
    • SINE KPT-330
  • Drug: carfilzomib
    Given IV
    Other Names:
    • Kyprolis
    • PR-171
  • Drug: dexamethasone
    Given PO or IV
    Other Names:
    • Aeroseb-Dex
    • Decaderm
    • Decadron
    • DM
    • DXM
Study Arms  ICMJE Experimental: Selinexor, carfilzomib, dexamethasone
Patients receive selinexor PO, carfilzomib IV, and dexamethasone PO QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: selinexor
  • Drug: carfilzomib
  • Drug: dexamethasone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2018)
100
Original Estimated Enrollment  ICMJE
 (submitted: July 22, 2014)
48
Estimated Study Completion Date  ICMJE April 2019
Estimated Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent in accordance with federal, local, and institutional guidelines
  • Aged 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Diagnosis of multiple myeloma as per International Myeloma Working Group (IMWG) uniform criteria
  • Measurable disease by IMWG as defined by at least one of the following:

    • Serum M-protein >= 0.5 g/dL
    • Urine M-protein >= 200 mg in a 24-hour collection
    • Serum free light chain level >= 10 mg/dL provided the free light chain ratio is abnormal
    • Measurable plasmacytoma; if plasmacytoma measurement is the only measurable disease, subject eligibility must be reviewed with lead principal investigator (PI) prior to signing consent
  • Relapsed/refractory multiple myeloma with progressive disease at study entry
  • Subjects must have been treated with at least 2 prior therapies including a proteasome inhibitor and a cereblon-binding agent

    • Subjects who are refractory to carfilzomib may enroll throughout the trial; carfilzomib refractory status is defined by IMWG criteria: disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in patients who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course
  • Ability to adhere with the study visit schedule and other protocol procedures
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L; screening ANC should be independent of growth factor support for over one week for all patients
  • Hemoglobin >= 8 g/dL; subjects may receive red blood cell transfusions as clinically indicated per institutional guidelines but screening hemoglobin should be independent of red blood cell transfusion for at least 3 days prior to cycle 1 day 1
  • Platelet count >= 50,000mm^3; platelet count should be independent of transfusions for at least 14 days for eligibility
  • Total bilirubin =< 2 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 times ULN)
  • Alanine aminotransferase (ALT) =< 2.5 times ULN; in the case of known (radiological and/or biopsy documented) liver metastasis, ALT =< 2.5 times ULN is acceptable
  • Estimated creatinine clearance of >= 30 mL/min, calculated using the formula of Cockroft and Gault
  • Female patients of child-bearing potential must agree practice abstinence or use dual methods of contraception during treatment and for 90 days after last dose of study drug.
  • Female patients of child-bearing potential must have negative pregnancy test at screening
  • Male patients must agree practice abstinence or use effective barrier methods of contraception during treatment and for 90 days after last dose of study drug
  • Male patients must agree not to donate semen or sperm treatment and for 90 days after last dose of carfilzomib

Exclusion Criteria:

  • Patients who are pregnant or lactating
  • Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =< 2 weeks prior to cycle 1 day 1
  • Concurrent therapy with approved or investigational anticancer therapeutic other than steroids
  • Major surgery within four weeks before cycle 1 day 1
  • Unstable angina or myocardial infarction within 4 months prior to randomization, New York Heart Association (NYHA) class III or IV heart failure, left ventricular ejection fraction (LVEF) < 40%, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias including uncontrolled chronic atrial fibrillation/atrial flutter, history of torsades de pointe, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemaker
  • Subject has plasma cell leukemia or Waldenstrom's macroglobuleinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis
  • Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization
  • Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within 14 days prior to first dose; patients with controlled infection or on prophylactic antibiotics are permitted in the study
  • Known to be human immunodeficiency virus (HIV) seropositive
  • Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus (HCV) ribonucleic acid (RNA) or HBsAg (hepatitis B virus [HBV] surface antigen)
  • Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
  • Patients with markedly decreased visual acuity in the opinion of the treating investigator after completion of screening ophthalmologic exam
  • Significant neuropathy (grades 3-4, or grade 2 with pain) within 14 days prior to randomization
  • Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
  • Any underlying condition that would significantly interfere with the absorption of an oral medication
  • Serious psychiatric or medical conditions that could interfere with treatment
  • Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
  • Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization
  • Patients with coagulation problems and active bleeding in the last month prior to cycle 1 day 1 (peptic ulcer, epistaxis, spontaneous bleeding)
  • Previous Selinexor exposure
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02199665
Other Study ID Numbers  ICMJE IRB14-0033
NCI-2014-01199 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
IRB14-0033 ( Other Identifier: University of Chicago )
P30CA014599 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Chicago
Study Sponsor  ICMJE University of Chicago
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Andrzej Jakubowiak University of Chicago
PRS Account University of Chicago
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP