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

Status: Active

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.

Eligibility Criteria

Inclusion Criteria

  • Written informed consent in accordance with federal, local, and institutional guidelines
  • 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 * In the twice weekly dosing cohort of the study, enrollment will be limited to patients meeting carfilzomib refractory status * In the weekly dosing cohort, it will be required that one of the expansion cohorts (20 subjects) enrolls carfilzomib refractory subjects and the other (20 subjects) enrolls carfilzomib/proteasome inhibitor (PI) naive/sensitive subjects
  • 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 >= 50,000 mm^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) (within 14 days prior to cycle 1 day 1)
  • 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 (within 14 days prior to cycle 1 day 1)
  • Estimated creatinine clearance of >= 30 mL/min (within 14 days prior to cycle 1 day 1), calculated using the formula of Cockcroft and Gault
  • Female patients of child-bearing potential must agree to practice abstinence or use dual methods of contraception during treatment and for 30-days after the last dose of carfilzomib and have a negative serum pregnancy test at screening
  • Male patients must agree to practice abstinence or use an effective barrier method of contraception during treatment and for 30-days after the last dose of carfilzomib 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
  • Male patients must agree not to donate semen or sperm while they are taking carfilzomib and 28 days after the last carfilzomib 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 (localized radiation to a single site at least 1 week before cycle 1 day 1 is permissible)
  • 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 macroglobulinemia 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

Locations & Contacts

Arizona

Scottsdale
Mayo Clinic in Arizona
Status: Temporarily closed to accrual
Contact: Keith Stewart
Email: stewart.keith@mayo.edu

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Active
Contact: Andrzej J. Jakubowiak
Phone: 773-834-1592
Email: ajakubowiak@medicine.bsd.uchicago.edu

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Temporarily closed to accrual
Contact: Craig Emmitt Cole
Phone: 734-936-5513
Detroit
Wayne State University / Karmanos Cancer Institute
Status: Active
Contact: Jeffrey Allan Zonder
Phone: 800-527-6266

New York

New York
Mount Sinai Hospital
Status: Active
Contact: Ajai Chari
Email: ajai.chari@mountsinai.org

Trial Objectives and Outline

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).

EXPLORATORY OBJECTIVES:

I. To perform an exploratory evaluation of pharmacodynamics.

II. To study the effects of treatment on the levels of: 1) exportin 1 (XPO1); 2) markers of apoptosis such as poly [ADP-Ribose] polymerase (PARP) and caspase 3, and; 3) markers of autophagy including caspase 10 and LC3B; 4) total protein levels and nuclear localization of tumor suppressor proteins (e.g. tumor protein 53 [p53], p21, retinoblastoma-associated protein [pRB], tumor protein p73 [p73]), growth regulatory proteins (e.g. I Kappa B [IkB]) and oncogenic proteins (e.g. v-MYC myelocytomatosis viral oncogene homolog [avian] [MYC]).

III. Study the effects of treatment on XPO1 expression in peripheral blood mononuclear cells (PBMCs) at day 1 and day 15 of cycle 1, and at the time of progression/relapse.

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

COHORT I: 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 of courses 1-8 and days 1, 2, 15, and 16 of courses 9+. Patients also receive 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.

COHORT II: Patients receive selinexor PO QD on days 1, 8, 15, and 22, carfilzomib IV over 30 minutes on days 1, 8, and 15 of courses 1-8 and days 1 and 15 of courses 9+. Patients also receive dexamethasone PO QD on days 1, 2, 8, 9, 15, 16, 22, and 23 of course 1 and days 1, 8, 15, and 22 of courses 2+. 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 Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Andrzej J. Jakubowiak

Trial IDs

Primary ID IRB14-0033
Secondary IDs NCI-2014-01199, KPT-CFZ
Clinicaltrials.gov ID NCT02199665