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

Information source: University of Chicago
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Refractory Multiple Myeloma

Intervention: selinexor (Drug); carfilzomib (Drug); dexamethasone (Drug); laboratory biomarker analysis (Other); pharmacological study (Other); questionnaire administration (Other)

Phase: Phase 1

Status: Recruiting

Sponsored by: University of Chicago

Official(s) and/or principal investigator(s):
Andrzej Jakubowiak, Principal Investigator, Affiliation: University of Chicago


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.

Clinical Details

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

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: 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

Secondary outcome:

Incidence of toxicities related to the combination of selinexor and carfilzomib assessed using NCI CTCAE version 4.0

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

Incidence of toxicities assessed using NCI CTCAE version 4.0

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). III. To perform pharmacokinetic studies at first cycle for each dose level for both selinexor and carfilzomib, and compare the results to those from their respective single arm trials. TERTIARY OBJECTIVES: I. To perform an exploratory evaluation of pharmacodynamics. II. To study the effects of treatment on exportin 1 (XPO1) expression in peripheral blood mononuclear cells (PBMCs) at day 1 and day 15 of cycle 1, and at the time of progression/relapse. III. To assess clinical response in standard and high-risk prognostic subgroups based on cytogenetics and gene expression profiling. OUTLINE: This is a dose-escalation study of selinexor and carfilzomib. Patients receive selinexor orally (PO) once daily (QD) on days 1, 3, 8, 10, 15, and 17, carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15, and 16, and dexamethasone PO QD or IV on days 1, 2, 8, 9, 15, 16, 22, and 23. 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.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


Inclusion Criteria:

- Written informed consent in accordance with federal, local, and institutional


- 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


- 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

- In the expansion cohort of the study, enrollment will be limited to patients

meeting carfilzomib refractory status

- 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 to use dual methods of

contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential; acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal; for both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose 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

- Participation in an investigational anti-cancer study within 30 days prior to cycle 1

day 1

- Concurrent therapy with approved or investigational anticancer therapeutic other than


- 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

- Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to


- 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


- Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize


- 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)

Locations and Contacts

Mt. Sinai, Chicago, Illinois, United States; Recruiting
Katherine Yung, Email: katherine.yung@mssm.edu

University of Chicago, Chicago, Illinois 60637, United States; Recruiting
Andrzej J. Jakubowiak, Phone: 773-702-1345, Email: ajakubowiak@medicine.bsd.uchicago.edu
Andrzej J. Jakubowiak, Principal Investigator

Additional Information

Starting date: June 2014
Last updated: August 4, 2015

Page last updated: August 23, 2015

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