Treatment of Selinexor in Combination With Clarithromycin, Pomalidomide and Dexamethasone for Relapsed Refractory Multiple Myeloma Patients
Condition: Myeloma Multiple; Myeloma; Refractory Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Selinexor; Clarithromycin; Pomalidomide; Dexamethasone
Intervention description: Given as 60 mg oral capsule; Given as 500 mg oral capsule; Given as 4 mg oral capsule; Given as 40 mg oral capsule
Intervention MeSH terms: Clarithromycin; Dexamethasone; Pomalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 74 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to determine the efficacy and safety of investigational
      combination therapy of Selinexor, Clarithromycin, Pomalidomide and Dexamethasone (ClaSPd) for
      patients with relapsed/refractory multiple myeloma. The hypothesis is that the addition of
      Selinexor to Clarithromycin, Pomalidomide and Dexamethasone will increase the overall
      response rate of patients with relapsed/refractory multiple myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent in accordance with federal, local, and institutional
             guidelines.

          -  Age ≥18 and <75 years at the time of informed consent.

          -  Confirmed diagnosis of multiple myeloma

          -  Symptomatic multiple myeloma per IMWG guidelines.

          -  Measurable disease as defined by at least one of the following: a. Serum M-protein ≥
             0.5 g/dL by serum protein electrophoresis (SPEP) or, for IgA myeloma, by quantitative
             IgA, and/or b. Urinary M-protein excretion at least 200 mg/24 hours, and/or c. Serum
             FLC ≥ 100 mg/L, provided that FLC ratio is abnormal, and/or d. If serum protein
             electrophoresis is felt to be unreliable for routine M-protein measurement (e.g., for
             IgA MM), then quantitative Ig levels by nephelometry or turbidimetry are acceptable.

          -  Relapsed and refractory multiple myeloma with documented evidence of PD after
             achieving at least SD for ≥ 1 cycle during a previous MM regimen (i.e., relapsed MM),
             and ≤ 25% response (i.e., patients never achieved ≥ MR) or PD during or within 60 days
             from the end of the most recent MM regimen (i.e., refractory MM).

          -  Previously received one to four prior lines of therapy and be pomalidomide-naïve.

        Exclusion Criteria:

          -  Documented active systemic light chain amyloidosis.

          -  Active plasma cell leukemia.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status greater than 2.

          -  Persistent non-hematological toxicity (except for peripheral neuropathy) from a prior
             treatment which has not resolved to at least Grade 2 or better by Cycle 1 Day 1
             (C1D1).

          -  Severe hepatic dysfunction with either: a. Total bilirubin > 2x ULN (> 3x ULN in
             subjects with Gilbert's syndrome [hereditary indirect hyperbilirubinemia]), and/or b.
             AST and/or ALT > 2.5x ULN

          -  Severe renal dysfunction with an estimated creatinine clearance of < 15 mL/min
             calculated using the Cockcroft and Gault formula.

          -  Impaired hematopoietic function with either: a. White blood cell count < 1,500/mm3,
             and/or b. Absolute neutrophil count < 1000/mm3, and/or c. Hemoglobin < 8.0 g/dL,
             and/or d. Platelet count < 100,000/mm3 (for patients in whom ≥ 50% of bone marrow
             nucleated cells are plasma cells, platelets ≥ 75,000/mm3 are acceptable).

          -  Blood (or blood product) transfusions or blood growth factors within 7 days of C1D1.
             Use of hematopoietic growth factor support is acceptable, including erythropoietin
             (EPO), darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte
             macrophage colony stimulating factor (GM-CSF), and platelet stimulators (e.g.,
             eltrombopag or romiplostim). However, patients must be platelet transfusion
             independent for > 1 week in order to be enrolled in the study.

          -  Radiation, chemotherapy or immunotherapy, or any other anticancer therapy within 2
             weeks prior to C1D1, or radio-immunotherapy within 6 weeks prior to C1D1. Patients on
             long-term glucocorticoids during Screening do not require a washout period. Prior
             radiation is permitted for treatment of fractures or to prevent fractures, as well as
             for pain management.

          -  Patients with history of spinal cord compression with residual paraplegia.

          -  Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1.

          -  Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell
             transplantation < 3 months prior to C1D1.

          -  Active graft versus host disease after allogeneic stem cell transplantation.

          -  Life expectancy < 3 months.

          -  Major surgery within 4 weeks prior to C1D1.

          -  Active, unstable cardiovascular function with either: a. Symptomatic ischemia, b.
             Uncontrolled clinically significant conduction abnormalities (e.g., patients with
             ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree
             atrioventricular (AV) block or asymptomatic left anterior fascicular block/right
             bundle branch block (LAFB/RBBB) will not be excluded), c. Congestive heart failure
             (CHF) of New York Heart Association (NYHA) Class ≥ 3, d. Myocardial infarction (MI)
             within 6 months prior to C1D1, or e. Screening 12-lead ECG showing a baseline QT
             interval as corrected by Bazett's formula (QTc) > 470 msec

          -  Uncontrolled active hypertension

          -  Venous thromboembolism within 6 months prior to C1D1 or a known inherited
             thrombophilia

          -  Inability to receive either prophylactic or therapeutic anticoagulation as determined
             appropriate by the Investigator

          -  Uncontrolled active infection requiring parenteral antibiotics, antivirals, or
             antifungals within one week prior to C1D1

          -  Any active gastrointestinal dysfunction that prevents the patient from swallowing
             tablets or interferes with absorption of study treatment

          -  Currently pregnant or breastfeeding. Lactating females must agree not to breast feed
             while receiving selinexor, pomalidomide and/or clarithromycin

          -  A serious psychiatric or medical condition which, in the opinion of the Investigator,
             could interfere with treatment

          -  Hypersensitivity or contraindication to selinexor, pomalidomide, dexamethasone and/or
             clarithromycin

          -  Prior exposure to a SINE compound, including selinexor

          -  Concomitant use of any strong CYP3A4 and/or CYP1A2 inhibitors (see Appendix 1)

          -  Unable to obtain commercial clarithromycin, pomalidomide and dexamethasone through a
             regular and/or specialty pharmacy.

          -  Unable or unwilling to register into the mandatory POMALYST REMSTM program and comply
             with its requirements.

          -  Male and female patients unwilling or unable to use effective methods of contraception
             throughout the study and for three months following the last dose. 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. Note that
             female patients of childbearing 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.