Clinical Trials /

Selinexor and Backbone Treatments of Multiple Myeloma Patients

NCT02343042

Description:

This study will independently assess the efficacy and safety of six combination therapies for the treatment of patients with Relapsed/Refractory Multiple Myeloma (RR MM) and Newly Diagnosed Multiple Myeloma (NDMM). The combinations to be evaluated include: selinexor + pomalidomide + dexamethasone (SPd), selinexor + bortezomib + dexamethasone (SVd), selinexor + lenalidomide + dexamethasone (SRd), selinexor + pomalidomide + dexamethasone + bortezomib (SPVd), selinexor + daratumumab + dexamethasone (SDd), and selinexor + carfilzomib + dexamethasone (SKd). The abbreviations for combination treatments have been revised to use V (Velcade) for bortezomib, R (Revlimid) for lenalidomide, D (Darzalex) for daratumumab, and K (Kyprolis) for carfilzomib.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Selinexor and Backbone Treatments of Multiple Myeloma Patients
  • Official Title: A Phase 1b/2 Study of Selinexor (KPT-330) in Combination With Backbone Treatments for Relapsed/Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: KCP-330-017
  • NCT ID: NCT02343042

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
SelinexorKPT-3301: Selinexor, Low-dose Dexamethasone & Pomalidomide (SPd)
DexamethasoneDecadron1: Selinexor, Low-dose Dexamethasone & Pomalidomide (SPd)
LenalidomideREVLIMID3: Selinexor, Low-dose dexamethasone, & Lenalidomide (SRd)
PomalidomidePomalyst1: Selinexor, Low-dose Dexamethasone & Pomalidomide (SPd)
BortezomibVelcade2: Selinexor, Low-dose Dexamethasone & Bortezomib (SVd)
DaratumumabDarzalex5: Selinexor, Low-dose dexamethasone, & Daratumumab (SDd)
CarfilzomibKyprolis6: Selinexor, Low-dose Dexamethasone, & Carfilzomib (Skd)

Purpose

This study will independently assess the efficacy and safety of six combination therapies for the treatment of patients with Relapsed/Refractory Multiple Myeloma (RR MM) and Newly Diagnosed Multiple Myeloma (NDMM). The combinations to be evaluated include: selinexor + pomalidomide + dexamethasone (SPd), selinexor + bortezomib + dexamethasone (SVd), selinexor + lenalidomide + dexamethasone (SRd), selinexor + pomalidomide + dexamethasone + bortezomib (SPVd), selinexor + daratumumab + dexamethasone (SDd), and selinexor + carfilzomib + dexamethasone (SKd). The abbreviations for combination treatments have been revised to use V (Velcade) for bortezomib, R (Revlimid) for lenalidomide, D (Darzalex) for daratumumab, and K (Kyprolis) for carfilzomib.

Detailed Description

      Multi-center, open-label, randomized (for dose schedule) clinical study with dose escalation
      (Phase 1) and expansion (Phase 2) stages to independently assess the maximum tolerated dose
      (MTD,) efficacy, and safety of selinexor + pomalidomide + dexamethasone (SPd), selinexor +
      bortezomib + dexamethasone (SVd), selinexor + lenalidomide + dexamethasone (SRd), selinexor +
      pomalidomide + dexamethasone + bortezomib (SPVd), selinexor + daratumumab + dexamethasone
      (SDd), and selinexor + carfilzomib + dexamethasone (SKd) in patients with relapsed/refractory
      multiple myeloma (RR MM) and newly diagnosed multiple myeloma (ND MM).

      SPVd arm will not open for enrollment until further notice.
    

Trial Arms

NameTypeDescriptionInterventions
1: Selinexor, Low-dose Dexamethasone & Pomalidomide (SPd)ExperimentalPomalidomide will be dosed at 4 mg daily for 21 days per cycle. Cohort 1.1: Selinexor 80 mg with dexamethasone 40 mg once weekly. Cohort 1.2: Selinexor 60 mg with dexamethasone 20 mg twice weekly; dexamethasone 40 mg weekly will also be given (without selinexor) on Days 22 & 24.
  • Selinexor
  • Dexamethasone
  • Pomalidomide
2: Selinexor, Low-dose Dexamethasone & Bortezomib (SVd)ExperimentalOne cycle is either 21 or 35 days (depending on bortezomib dosing schedule). Cohort 2.1: Selinexor 80 mg with dexamethasone 40 mg once weekly. Bortezomib 1.3 mg/m2 subcutaneous (SC) once weekly. Cohort 2.2: Selinexor 60 mg with dexamethasone 20 mg twice weekly; dexamethasone 40 mg weekly will also be given on Days 29 and 31. Bortezomib 1.3 mg/m2 SC dosed once weekly.
  • Selinexor
  • Dexamethasone
  • Bortezomib
3: Selinexor, Low-dose dexamethasone, & Lenalidomide (SRd)ExperimentalLenalidomide at 25mg daily for 21 days per 28 day cycle. Cohort 3.1: Selinexor 80mg with dexamethasone 40mg once weekly. Cohort 3.2: Selinexor 60mg with dexamethasone 20mg twice weekly; dexamethasone 40mg weekly will also be given (without selinexor) on Days 22 and 24.
  • Selinexor
  • Dexamethasone
  • Lenalidomide
4:Selinexor,Low-dose dexamethasone,Pomalidomide,Velcade (SPVd)ExperimentalCohort 4.1: Selinexor 100 mg with dexamethasone 40 mg once weekly. Pomalidomide at 4 mg daily for 21 days per 28 day cycle. Bortezomib 1.3 mg/m2 subcutaneous (SC) once weekly. Cohort 4.2: Selinexor 60 mg with dexamethasone 20 mg twice weekly. Pomalidomide at 4 mg daily for 21 days per 28 day cycle. Bortezomib 1.3 mg/m2 subcutaneous (SC) once weekly. Note: This arm is not open for enrollment at any institution in this study.
  • Selinexor
  • Dexamethasone
  • Pomalidomide
  • Bortezomib
5: Selinexor, Low-dose dexamethasone, & Daratumumab (SDd)ExperimentalDaratumumab at 16 mg/kg IV every week for cycles 1 and 2; then every 2 weeks for cycles 3-6, then once a month for cycles 6 and beyond. Cohort 5.1: Selinexor 100 mg once weekly, with dexamethasone or equivalent dose of other corticosteroid, given intravenously or by mouth, 40 mg weekly in single or divided doses. Cohort 5.2: Selinexor 60 mg twice weekly with dexamethasone or equivalent dose of other corticosteroid, given intravenously or by mouth, 40 mg weekly in single or divided doses.
  • Selinexor
  • Dexamethasone
  • Daratumumab
6: Selinexor, Low-dose Dexamethasone, & Carfilzomib (Skd)ExperimentalCohort 6.1: Selinexor 100 mg with dexamethasone 40 mg once weekly. Carfilzomib 56 mg/m2 IV once weekly per 28 day cycle.
  • Selinexor
  • Dexamethasone
  • Carfilzomib
7: Selinexor,Low-dose Dexamethasone,Lenalidomide (SRd) NDMMExperimentalCohort 7.1 in Newly Diagnosed MM: Selinexor 60 mg with dexamethasone 40 mg once weekly. Lenalidomide at 25 mg daily for 21 days per 28 day cycle.
  • Selinexor
  • Dexamethasone
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent in accordance with federal, local, and institutional
             guidelines.

          2. Age ≥ 18 years at the time of informed consent

          3. Histologically confirmed diagnosis, measurable disease and evidence of disease
             progression of MM, as described below.

          4. Symptomatic MM, based on IMWG guidelines. Patients must have measurable disease as
             defined by at least one of the following:

               1. Serum M-protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) or, for IgA
                  myeloma, by quantitative IgA

               2. Urinary M-protein excretion at least 200 mg/24 hours

               3. Serum FLC ≥ 100 mg/L, provided that FLC ratio is abnormal

               4. 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
                  turbidometry are acceptable.

          5. Any non-hematological toxicities (except for peripheral neuropathy as described in
             exclusion criterion #24) that patients experienced from treatments in previous
             clinical studies must have resolved to ≤ Grade 2 by Cycle 1 Day 1.

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

          7. Adequate hepatic function within 21 days prior to C1 D1:

               -  For SPd and SRd: Total bilirubin < 2x ULN (except patients with Gilbert's
                  syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin
                  of ≤ 3x ULN) and both AST and ALT < 2.5x ULN)

               -  For SVd, SPVd and SDd): Total bilirubin of ≤ 1.5x ULN (except patients with
                  Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total
                  bilirubin of ≤ 3x ULN) and both AST and ALT < 2.0x ULN)

               -  For SKd: Total bilirubin < 2x ULN (except patients with Gilbert's syndrome
                  [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3x
                  ULN) and both AST and ALT < 3.0x ULN

          8. Adequate renal function within 21 days prior to C1 D1:

               -  Estimated creatinine clearance of (calculated using the formula of Cockroft and
                  Gault):

               -  ≥ 20 mL/min for SVd, SPVd, and SDd Arms

               -  ≥ 45 mL/min for SPd Arm (as requested by the manufacturer)

               -  > 50 mL/min for SRd Arm

          9. Adequate hematopoietic function within 21 days prior to C1 D1: total white blood cell
             (WBC) count ≥ 1,500/mm3, ANC ≥ 1000/mm3, hemoglobin (Hb) ≥ 8.0 g/dL, and platelet
             count ≥ 75,000/mm3. For expansion cohorts only, platelet counts > 50,000/mm3; for
             patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells, platelets or ≥
             30,000/mm3 are acceptable for expansion cohorts. Patients receiving hematopoietic
             growth factor support, including erythropoietin (EPO), darbepoetin, granulocyte-colony
             stimulating factor (G-CSF), granulocyte macrophagecolony stimulating factor (GM-CSF),
             and platelet stimulators (e.g., eltrombopag or romiplostim) may continue to do so.
             However, patients in the escalation cohorts must be platelet transfusion independent
             for > 1 week in order to be enrolled in the study.

         10. Female patients of child-bearing potential must agree to use dual methods of
             contraception and have a negative serum pregnancy test at Screening. Male patients
             must use an effective barrier method of contraception 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. For both male and female patients, effective
             methods of contraception must be used throughout the study and for three months
             following the last dose.

             SPd (Arm 1) Only:

         11. Relapsed and refractory MM with:

               1. Documented evidence of PD after achieving at least SD for ≥ 1 cycle during a
                  previous MM regimen (i.e., relapsed MM)

               2. ≤ 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)

               3. Previously undergone ≥ 2 cycles of lenalidomide and a proteasome inhibitor (in
                  separate therapeutic regimens [not for maintenance] or in combination)

               4. In the expansion arm at RP2D, patients must not be pomalidomide refractory

             SVd (Arm 2) Only:

         12. Relapsed or refractory MM with

               1. Documented evidence of relapse after ≥ 1 previous line of therapy

               2. Not refractory to bortezomib in their most recent line of therapy

             SRd in RRMM (Arm 3) Only:

         13. Patients who received ≥ 1 prior therapeutic regimen (prior lenalidomide is allowed as
             long as patient's MM was not refractory to prior lenalidomide; patients whose MM was
             refractory to lenalidomide maintenance regimens will be allowed in this cohort).

             SPVd (Arm 4) Only:

         14. Patients whose MM is relapsing after ≥ 1 prior therapy with progression on their last
             therapy.

             SDd (Arm 5) Only:

         15. Patients who received ≥ 3 prior lines of therapy, including a PI and an IMiD, or
             patients with MM refractory to both a PI and an IMiD.

         16. Patients must not have received prior daratumumab therapy (Cohort 5.3 ONLY - dose
             expansion at RP2D).

             SKd (Arm 6) Only:

         17. Patients may have received prior bortezomib or carfilzomib therapy, however their MM
             must NOT be refractory to carfilzomib.

             SRd in NDMM (Arm 7) Only:

         18. Patients must have symptomatic myeloma per IMWG guidelines with either CRAB criteria
             or Myeloma Defining Events and need systemic therapy.

         19. No prior systemic therapy for NDMM is permitted other than pulse dose dexamethasone
             (maximum dose of 160 mg).

        Exclusion Criteria:

        Patients meeting any of the following exclusion criteria are not eligible to enroll in this
        study:

          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 plasma cell leukemia

          5. Blood (or blood product) transfusions and blood growth factors within 7 days of C1D1
             (only for patients enrolling into the Expansion Phase)

          6. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks
             prior to C1D1, and 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

          7. Patients with history of SCC with residual paraplegia (Dose Escalation Phase only).

          8. Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1

          9. Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell
             transplantation < 3 months prior to C1D1

         10. Active graft versus host disease after allogeneic stem cell transplantation

         11. Life expectancy < 3 months

         12. Major surgery within 4 weeks prior to C1D1

         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 C1D1

               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. Any active gastrointestinal dysfunction that prevents the patient from swallowing
             tablets or interferes with absorption of study treatment

         19. Currently pregnant or breastfeeding

         20. A serious psychiatric or medical condition which, in the opinion of the Investigator,
             could interfere with treatment

         21. Hypersensitivity to any of the treatments for the Arm in which the patient is enrolled

         22. In the SVd (Arm 2) only: Prior history of neuropathy Grade > 2, or Grade 2 neuropathy
             with pain at screening (within 21 days prior to C1D1)

         23. Prior exposure to a SINE compound, including selinexor
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1 (Dose-escalation)
Time Frame:12 months
Safety Issue:
Description:Determine the maximum tolerated dose (MTD) for once weekly (QW) and twice weekly (BIW) selinexor dose Cohorts in the 7 Arms being evaluated.

Secondary Outcome Measures

Measure:Phase 1 (Dose-escalation)
Time Frame:12 months
Safety Issue:
Description:Evaluate safety and tolerability (per Arm) using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Measure:Phase 2 (Expansion)
Time Frame:12 months
Safety Issue:
Description:• Assess time to progression (TTP), progression-free survival (PFS), and overall survival (OS) for each Arm.
Measure:Phase 2 (Expansion)
Time Frame:12 months
Safety Issue:
Description:Assess safety, tolerability, and incidence of adverse events (AEs) per CTCAE version 4.03 for each Arm.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Karyopharm Therapeutics Inc

Trial Keywords

  • Selinexor
  • KCP-330
  • STOMP
  • Multiple Myeloma
  • Relapsed/Refractory
  • Dexamethasone
  • Pomalidomide
  • Bortezomib
  • Karyopharm
  • Lenalidomide
  • Daratumumab
  • Newly Diagnosed
  • Carfilzomib

Last Updated

December 31, 2019