A Phase 1b/2 Study of Selinexor (KPT-330) in Combination With Backbone Treatments for Relapsed/Refractory Multiple Myeloma

This study will independently assess the efficacy and safety of two combination therapies for the treatment of patients with relapsed/refractory multiple myeloma (RR MM): selinexor + dexamethasone + pomalidomide (SdP) and selinexor + dexamethasone + bortezomib (SdB).
Cancer (Oncology) - Multiple Myeloma, Cancer (Oncology)
William Bensinger, MD
Swedish Cancer Institute
Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed diagnosis, measurable disease and evidence of disease progression of MM, as described below.
  2. Symptomatic MM, based on IMWG guidelines. Patients must have measurable disease as defined by at least one of the following:

    • Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or, for IgA myeloma, by quantitative IgA
    • Urinary M-protein excretion at least 200 mg/24 hours
    • Serum FLC ≥ 100 mg/L, provided that FLC ratio is abnormal
    • If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative Ig levels by nephelometry or turbidometry are acceptable.
  3. Any non-hematological toxicities (except for peripheral neuropathy as described in exclusion criterion #22) that patients experienced from treatments in previous clinical studies must have resolved to ≤ Grade 2 by Cycle 1 Day 1.
  4. Adequate hepatic function within 21 days prior to C1 D1:
  5. Adequate renal function within 21 days prior to C1 D1:
  6. Adequate hematopoietic function within 21 days prior to C1 D1:
  7. SdP (Arm 1) Only:

    Relapsed and refractory MM with:

    • Documented evidence of PD after achieving at least SD for ≥ 1 cycle during a previous MM regimen (i.e., relapsed MM)
    • ≤ 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 undergone ≥ 2 cycles of lenalidomide and a proteasome inhibitor (in separate therapeutic regimens [not for maintenance] or in combination)
  8. SdB (Arm 2) Only:

Relapsed or refractory MM with:

  • Documented evidence of relapse after ≥ 1 previous line of therapy
  • Not refractory to bortezomib in their most recent line of therapy 9. SdL (Arm 3) Only:
  • Patients who received ≥ 1 prior therapeutic regimen (prior lenalidomide is allowed as long as patient was not refractory to prior lenalidomide)

Exclusion Criteria:

  1. Smoldering MM.
  2. MM that does not express M-protein or FLC (i.e., non-secretory MM is excluded), and quantitative immunoglobulin levels cannot be used instead
  3. Documented active systemic amyloid light chain amyloidosis
  4. Active MM involving the central nervous system (CNS)
  5. Active plasma cell leukemia
  6. Blood (or blood product) transfusions and blood growth factors within 7 days of C1 D1 only for patients enrolling into the Expansion Phase
  7. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to C1 D1, and radio-immunotherapy within 6 weeks prior to C1 D1. Patients on long-term glucocorticoids during Screening, including use for spinal cord compression, do not require a washout period. Prior radiation is permitted for treatment of fractures or to prevent fractures as well as for pain management
  8. Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1 D1
  9. Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell transplantation < 3 months prior to C1 D1
  10. Active graft versus host disease after allogeneic stem cell transplantation
  11. A life expectancy of < 3 months
  12. Major surgery within 4 weeks prior to C1 D1
  13. Active, unstable cardiovascular function:

    1. Symptomatic ischemia, or
    2. 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), or
    3. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3, or
    4. Myocardial infarction (MI) within 3 months prior to C1 D1
    5. Ejection fraction (EF) < 50% at screening
  14. Uncontrolled active hypertension
  15. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose
  16. Known active hepatitis A, B or C
  17. Known HIV infection or HIV seropositivity
  18. Prior history of malignancies: cancer treated with curative intent > 5 years before study enrollment and without evidence of recurrence will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the medical monitor. Exceptions include:

    1. Resected basal or squamous cell carcinoma of the skin
    2. Carcinoma in situ of the cervix
  19. Any active gastrointestinal dysfunction that prevents the patient from swallowing tablets, or interferes with absorption of study treatment
  20. Currently pregnant or breastfeeding
  21. A serious psychiatric or medical condition which, in the opinion of the investigator, could interfere with treatment
  22. Hypersensitivity to any of the treatments for the Arm in which the patient is enrolled
  23. In the SdB (Arm 2)only:

    • Prior history of neuropathy Grade > 2, or Grade 2 neuropathy with pain at screening (within 21 days prior to C1 D1)
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