Selinexor for Lenalidomide-Refractory Patients

This is a pilot, multi-center, open-label study evaluating selinexor's ability to overcome resistance for multiple myeloma patients who are refractory to lenalidomide-containing therapies.

Enrollment:

The study will enroll up to a total of 22 Multiple Myeloma (MM) patients with progressive disease.

Study Assessments:

The study will consist of:

1. screening period;
2. study treatment until disease progression or intolerable toxicity;
3. a final assessment to occur up to 28 days after the end of the last treatment cycle; and
4. follow-up period.

The screening period will be conducted within 14 days before baseline (baseline being day 1 of cycle 1, before study drug administration). During this period, a medical history will be obtained along with complete physical examination including vital signs measurements, height, weight, Eastern Cooperative Oncology Group (ECOG) performance status, and 12-lead electrocardiogram (EKG). MM assessments will be performed, including β2 microglobulin (β2M), serum free light chain (SFLC) serum and urine protein electrophoresis, quantification of serum immunoglobulins, urine and serum immunofixation, and 24-hour total protein. An additional serum sample will be obtained for evaluation of biomarkers. In addition, a postero-anterior and lateral chest radiographs, skeletal survey, and a bone marrow aspirate (BM) and biopsy will be performed within 28 days of baseline. Clinical laboratory tests including hematology, clinical chemistry (blood urea nitrogen [BUN], serum creatinine, uric acid, lactate dehydrogenase [LDH], total bilirubin, alkaline phosphatase, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), electrolytes (potassium, sodium, chloride and calcium), random glucose, total protein, amylase, albumin, and urinalysis as well as serum pregnancy tests for females of child-bearing potential (FCBPs). Subjects will also be asked to fill out quality of life assessments at several time points during this study.

Subjects eligible for this study will receive treatment with study drug until disease progression or intolerable toxicity does not allow ongoing treatment.

Assessments:

Schedule of assessments: Subjects that meet the inclusion/exclusion criteria during the screening period will continue to Day 1 of Cycle 1, when baseline evaluations will be conducted. Subjects who continue to meet the inclusion/exclusion criteria will be enrolled in the trial and study drug will be administered. During Cycle 1, subjects will also have study visits during which assessments will be performed on Days 8, 15 and 22. MM assessments will be performed on Day 22 during all subsequent cycles. Starting with Cycle 2, study visits will take place on Days 1 and 22. See Table 1

Assessment overview: During the treatment period, each subject will have clinical laboratory tests performed to monitor for potential toxicity. Additional procedures performed at these visits will include monitoring for adverse events (AEs), review of concomitant medications and other support therapies (e.g. growth factors and transfusion), MM disease assessments, ECOG performance status, vital signs measurements, and physical examination. Subjects will remain on study until documentation of progressive disease (PD) as defined by the International Myeloma Working Group (IMWG) criteria. Subjects with stable disease will remain in the study. For subjects who show disappearance of urine and serum M-protein by protein electrophoresis and immunofixation on 2 consecutive assessments and the subject shows no other signs of disease activity, a bone marrow (BM) aspirate and biopsy will be required to confirm their CR. A BM aspirate and biopsy will not be required for subjects in any other response group categories.

Up to twenty-eight days after the last dose of study drug, subjects are to complete a final assessment (herein referred to as the End-of-Study treatment visit). Procedures to be conducted at this visit include a MM disease assessment, measurement of vital signs and weight, a complete physical examination, assessment of adverse events, a review of concomitant medications, assessment of ECOG performance status, hematology and clinical chemistry laboratory tests including electrolytes, total protein, amylase and albumin, and an assessment of response to treatment with the use of SFLC assay and ratio, serum and urine protein electrophoresis, quantification of serum immunoglobulins, urine and serum immunofixation, 24-hour total urine protein, and serum β2M. Subjects who withdraw from the study before the completion of the eight 28-day cycle evaluation periods will have all End- of-Study treatment assessments performed at their final visit.

Following the End-of-Study treatment visit, subjects will be monitored for PD and survival by clinic visits every 3 months and every 6 months, respectively, until alternate therapy needs to be started or death intervenes.

Dosing Regimens:

All subjects enrolled will receive (Dose Level 0) 1) selinexor, PO, at 60 mg once weekly on days 1, 8, 15, and 22 of a 28-days cycle, 2) lenalidomide, PO, 10 mg daily on days 1-21 of a 28-day cycle and 3) steroids at the same dose and schedule as the last lenalidomide-containing regimen if it contained steroids that they had failed to meet eligibility for this study.

Recommended Concomitant Therapy:

Subjects may receive full supportive care, including hydration prophylaxis, treatment with a 5-HT3 antagonist and/or other anti-nausea agents, antibiotics, antivirals, vitamins, and supplements as appropriate. Patients should receive anti-platelet therapy with baby aspirin or other agents if they have additional risk factors for developing thrombotic events.

Number of Patients (planned): 22

Study Population: Multiple myeloma patients who are refractory to a lenalidomide-containing therapy