Clinical Trials /

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

NCT02199665

Description:

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.

Related Conditions:
  • Multiple Myeloma
  • Plasmacytoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selinexor, Carfilzomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: IRB14-0033
  • SECONDARY ID: NCI-2014-01199
  • SECONDARY ID: IRB14-0033
  • SECONDARY ID: P30CA014599
  • NCT ID: NCT02199665

Conditions

  • Refractory Multiple Myeloma

Interventions

DrugSynonymsArms
selinexorCRM1 nuclear export inhibitor KPT-330, KPT-330, selective inhibitor of nuclear export KPT-330, SINE KPT-330Selinexor, carfilzomib, dexamethasone
carfilzomibKyprolis, PR-171Selinexor, carfilzomib, dexamethasone
dexamethasoneAeroseb-Dex, Decaderm, Decadron, DM, DXMSelinexor, carfilzomib, dexamethasone

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Selinexor, carfilzomib, dexamethasoneExperimentalPatients 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.
  • selinexor
  • carfilzomib
  • dexamethasone

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of selinexor, carfilzomib, and dexamethasone
Time Frame:28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description: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.
Measure:Incidence of toxicities assessed using NCI CTCAE version 4.0
Time Frame:Up to 28 days after completion of study treatment
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Last Updated

April 29, 2019