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

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.

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