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

Who is this study for? Patients with Multiple Myeloma
What treatments are being studied? Selinexor+Dexamethasone
Status: Recruiting
Location: See all (24) locations...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 1/Phase 2
SUMMARY

This study will independently assess the efficacy and safety of 10 combination therapies in 11 arms, in dose-escalation/-evaluation and expansion phases, for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM). The combinations to be evaluated are: Arm 1: Selinexor + dexamethasone + pomalidomide (SPd) Arm 2: Selinexor + dexamethasone + bortezomib (SVd); enrollment complete Arm 3: Selinexor + dexamethasone + lenalidomide (SRd) in RRMM; enrollment complete Arm 4: Selinexor + dexamethasone + pomalidomide + bortezomib (SPVd) Arm 5: Selinexor + dexamethasone + daratumumab (SDd); enrollment complete Arm 6: Selinexor + dexamethasone + carfilzomib (SKd) Arm 7: Selinexor + dexamethasone + lenalidomide (SRd) in NDMM Arm 8: Selinexor + dexamethasone + ixazomib (SNd) Arm 9: Selinexor + dexamethasone + pomalidomide + elotuzumab (SPEd) Arm 10: Selinexor + dexamethasone + belantamab mafodotin (SBd) Arm 11: Selinexor + dexamethasone + pomalidomide + daratumumab (SDPd) Selinexor pharmacokinetics: PK Run-in (Days 1-14): Starting in protocol version 8.0, patients enrolled to any arm in the Dose Escalation Phase (i.e., Arm 4 [SPVd], Arm 6 [SKd], Arm 8 [SNd], Arm 9 [SPEd], Arm 10 [SBd], and Arm 11 [SDPd]) will also first be enrolled to a pharmacokinetics (PK) Run-in period until 9 patients have been enrolled to this period to evaluate the PK of selinexor before and after co-administration with a strong CYP3A4 inhibitor.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: No
View:

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

• Age greater than or equal to (≥) 18 years at the time of informed consent.

• Histologically confirmed diagnosis with measurable disease for relapsed/refractory myeloma.

• 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 gram per deciliter (g/dL) by serum protein electrophoresis (SPEP) or, for immunoglobulin A (IgA) myeloma, by quantitative IgA

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

• Serum free light chain (FLC) ≥ 100 milligram per liter (mg/L), provided that FLC ratio is abnormal

• If SPEP is felt to be unreliable for routine M-protein measurement (example, for IgA MM), then quantitative immunoglobulin (Ig) levels by nephelometry or turbidometry are acceptable

• Any non-hematological toxicities (except for peripheral neuropathy as described in exclusion criterion #22) that patients had from treatments in previous clinical studies must have resolved to less than or equal (≤) Grade 2 by C1D1.

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

• Adequate hepatic function within 28 days prior to C1D1:

• For SPd, SRd, and SPEd: Total bilirubin < 2* upper limit of normal (ULN) (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3* ULN) and both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5* ULN

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

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

• Adequate renal function within 28 days prior to C1D1. Estimated creatinine clearance (CrCl) calculated using the formula of Cockroft and Gault (1976):

• ≥ 20 milliliter per minute (mL/min) for SVd, SDd, and SKd arms

• ≥ 30 mL/min for SNd and SBd arms

• ≥ 45 mL/min for SPd, SPVd, SPEd and SDPd arms

• > 60 mL/min for SRd arm

• Adequate hematopoietic function within 28 days prior to C1D1: total white blood cell (WBC) count ≥ 1,500/millimeter cube (mm^3), absolute neutrophil count (ANC) ≥ 1,000/mm^3, hemoglobin (Hb) ≥ 8.0 g/dL, and platelet count ≥ 100,000/mm^3.

• SPVd (Arm 4) and SKd (Arm 6) only: platelet count ≥150,000.

• Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment.

• SPd (Arm 1) Only:

• Relapsed or refractory MM with:

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

• ≤ 25 percent (%) 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 PI (in separate therapeutic regimens [not for maintenance] or in combination)

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

• SVd (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

• SRd in RRMM (Arm 3) Only:

• 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:

• Patients who received 1- 3 prior lines of therapy, including ≥ 2 cycles of lenalidomide and have demonstrated disease progression on their last therapy (may include prior bortezomib, as long as the patient's MM was not refractory to bortezomib therapy), but patients must be pomalidomide-naïve in the Dose Expansion at RP2D (Cohort 4.3 ONLY).

• SDd (Arm 5) Only:

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

• Patients must not have received prior anti-cluster of differentiation 38 (anti-CD38) monoclonal antibodies (Cohort 5.3 ONLY - Dose Expansion at RP2D).

• SKd (Arm 6) Only:

• Patients may have received prior PIs; however, their MM must NOT be refractory to carfilzomib.

• SRd in NDMM (Arm 7) Only:

• Patients must have symptomatic myeloma per IMWG guidelines with either CRAB criteria (calcium elevation, renal failure, anemia, lytic bone lesions) or myeloma-defining events and need systemic therapy. No prior systemic therapy for NDMM is permitted other than pulse dose dexamethasone (maximum dose of 160 mg) or corticosteroid equivalent.

• SNd (Arm 8) Only:

• Patients must have MM that relapsed after 1 - 3 prior lines of therapy (may not include those with MM refractory to bortezomib or carfilzomib but patients must be ixazomib-naïve).

• SPEd (Arm 9) Only:

• Patients who received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor (in separate or the same regimens), but patients must be pomalidomide-naive and elotuzumab-naive in the Dose Expansion at RP2D (Cohort 9.3 ONLY).

• SBd (Arm 10) Only:

• Patients who have MM that was refractory to an IMiD, a proteasome inhibitor, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody. Patients must be belantamab mafodotin-naive in the Dose Expansion cohort at RP2D (Cohort 10.3 ONLY).

• SDPd (Arm 11) Only:

• Patients who received 1-3 prior therapies, including lenalidomide and a proteasome inhibitor (in separate or the same regimen), but patients must be pomalidomide-naive and daratumumab-naive in the Dose Expansion cohort at RP2D (Cohort 11.3 ONLY).

Locations
United States
Arizona
Banner MD Anderson Cancer Center
Recruiting
Gilbert
California
Jonnsson Comprehensive Cancer Center / University of Los Angeles
Recruiting
Los Angeles
Colorado
Sarah Cannon-Colorado Blood Cancer Institute
Withdrawn
Denver
Massachusetts
Dana Farber Cancer Institute
Recruiting
Boston
Massachusetts General Hospital
Recruiting
Boston
North Carolina
University of North Carolina - Chapel Hill Comprehensive Cancer Center
Recruiting
Chapel Hill
Duke Institute of Cancer/ Duke University
Recruiting
Durham
Nebraska
University of Nebraska Medical Center
Recruiting
Omaha
New Jersey
Hackensack University Medical Center - John Theurer Cancer Center
Recruiting
Hackensack
New York
Columbia University
Recruiting
New York
Weill Cornell Medicine
Recruiting
New York
Wilmot Cancer Center/ University of Rochester
Recruiting
Rochester
Tennessee
Sarah Cannon- Tennessee Oncology Nashville
Recruiting
Nashville
Washington
Swedish Cancer Institute
Active, not recruiting
Seattle
Wisconsin
University of Wisconsin School of Medicine and Public Health
Recruiting
Madison
Other Locations
Canada
Tom Baker Cancer Center/Alberta Health Services
Withdrawn
Calgary
Cross Cancer Institute / University of Alberta
Recruiting
Edmonton
Queen Elizabeth II Health Sciences Center
Recruiting
Halifax
Maisonneuve-Rosemont Hospital
Active, not recruiting
Montreal
Royal Victoria Hospital / McGill University
Active, not recruiting
Montreal
Memorial Hospital of Newfoundland
Active, not recruiting
St. John's
Princess Margaret Cancer Centre
Recruiting
Toronto
Vancouver General Hospital
Withdrawn
Vancouver
Cancer Care Manitoba
Active, not recruiting
Winnipeg
Contact Information
Primary
Eric Sbar, DO
eric.sbar@karyopharm.com
Backup
Sharon Shacham, PhD
SShacham@karyopharm.com
Time Frame
Start Date: October 2015
Estimated Completion Date: January 2025
Participants
Target number of participants: 518
Treatments
Experimental: 1: Selinexor, Low-dose Dexamethasone and Pomalidomide (SPd)
Each cycle is of 28 days~Cohort 1.1: Selinexor (SEL) 60/80/100 mg orally (PO) once weekly (QW); Dexamethasone (DEX) 40 mg PO once weekly; Pomalidomide (POM) 2/3/4 mg PO Days 1-21.~Cohort 1.2: SEL 40/60/80 mg PO twice weekly (BIW); DEX 20 mg PO twice weekly; POM 3/4 mg PO Days 1-21.~Cohort 1.3: Selinexor, Dexamethasone and Pomalidomide will be dosed at RP2D-1.~Cohort 1.4: SEL 40 mg PO QW; DEX 40 mg PO QW; POM 4mg PO once daily (QD) Days 1-21.
Experimental: 2: Selinexor, Low-dose Dexamethasone and Bortezomib (SVd)
Each cycle is of 35 days~Cohort 2.1: SEL 60/80/100 mg PO once weekly; DEX 40 mg PO once weekly; Bortezomib (BOR) 1.3 milligram per meter square (mg/m^2) subcutaneous (SC) once weekly.~Cohort 2.2: SEL 40/60/80 mg PO twice weekly; DEX 20 mg PO twice weekly; BOR 1.3 mg/m^2 subcutaneous (SC) once weekly.~Cohort 2.3: Selinexor, Dexamethasone and Bortezomib will be dosed at RP2D-2.
Experimental: 3: Selinexor, Low-dose DEX, and Lenalidomide (SRd) in RRMM
Each cycle is of 28 days~Cohort 3.1: SEL 40/60/80/100 mg PO once weekly; DEX 40 mg PO once weekly; Lenalidomide (LEN) 15/25 mg PO Days 1-21.~Cohort 3.2: SEL 40/60/80 mg PO twice weekly; DEX 20 mg PO twice weekly; LEN 15/25 mg PO Days 1-21.~Cohort 3.3: Selinexor, Dexamethasone and Lenalidomide will be dosed at RP2D-3.
Experimental: 4:Selinexor, Low-dose dexamethasone, Pomalidomide, Velcade (SPVd)
PK Run-in Period: Selinexor and Clarithromycin:~For the first 9 patients enrolled into this dose escalation arm~14 day run-in period after which patients will proceed to Dose-Escalation Phase C1D1~Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8.~PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose.~Dose-escalation Phase:~All patients enrolled into this Arm~Each cycle is of 28 days.~Cohort 4.1:~SEL 40/60 mg PO once weekly; DEX 40 mg PO once weekly; POM 4 mg PO Days 1-21; BOR 1.3 mg/m^2 subcutaneous (SC) once weekly.~Cohort 4.3: Selinexor, Dexamethasone, Pomalidomide, Velcade (Bortezomib) will be dosed at RP2D-4.
Experimental: 5: Selinexor, Low-dose dexamethasone, and Daratumumab (SDd)
Each cycle is of 28 days~Cohort 5.1:~SEL 80/100 mg PO once weekly; DEX 40 mg once weekly (IV or PO); DARA: 16 mg/kg IV infusion Cycle 1-2: Once weekly, Cycle 3-6: Every other week, Cycle 6 and greater: Once a month.~Cohort 5.2:~SEL: 60 mg PO twice weekly; DEX: 40 mg weekly (IV or PO); DARA: 16 milligram per kilogram (mg/kg) IV infusion Cycle 1-2: Once. weekly, Cycle 3-6: Every other week, Cycle 6 and greater: Once a month.~Cohort 5.3: Selinexor, Dexamethasone and Daratumumab will be dosed at RP2D-5.
Experimental: 6: Selinexor, Low-dose dexamethasone, and Carfilzomib (SKd)
PK Run-in Period: Selinexor and Clarithromycin:~For the first 9 patients enrolled into this dose escalation arm~14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1~Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8.~PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose.~Dose-Escalation Phase:~All patients enrolled into this Arm~Each cycle is of 28 days~Cohort 6.1:~SEL 40/60/80/100 mg PO once weekly on days 1, 8, 15, and 22; DEX 40 mg IV or PO once weekly; Carfilzomib (CAR) 56 or 70 mg/m^2 IV infusion once weekly on days 1, 8, and 15.~Cohort 6.2:~SEL 60/80/100 mg PO once weekly on days 1, 8, and 15; DEX 40 mg IV or PO once weekly; CAR 56 or 70 mg/m^2 IV infusion once weekly on days 1, 8, and 15.~Cohort 6.3: Selinexor, Dexamethasone and Carfilzomib will be dosed at RP2D-6.
Experimental: 7: Selinexor, Low-dose DEX and Lenalidomide (SRd) in NDMM
Each cycle is of 28 days~Cohort 7.1:~SEL 40/60/80 mg PO once weekly; DEX 40 mg PO once weekly; LEN 25 mg PO Days 1-21.~Cohort 7.3: Selinexor, Dexamethasone and Lenalidomide will be dosed at RP2D-7.
Experimental: 8: Selinexor, Low-dose dexamethasone, and Ixazomib (SNd)
PK Run-in Period: Selinexor & Clarithromycin:~For the first 9 patients enrolled into this dose escalation arm~14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1~Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8.~PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose.~Dose-Escalation Phase:~All patients enrolled into this Arm~Each cycle is of 28 days~Cohort 8.1:~SEL 40/60/80/100 mg PO once weekly; DEX 20 mg PO twice weekly; IXA 3/4 mg PO once weekly.~Cohort 8.3: Selinexor, Dexamethasone and Ixazomib will be dosed at RP2D-8.
Experimental: 9: Selinexor, Low-dose DEX, Pomalidomide and Elotuzumab (SPEd)
PK Run-in Period: Selinexor and Clarithromycin:~For the first 9 patients enrolled into this dose escalation arm~14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1~Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8.~PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose.~Dose-Escalation Phase:~All patients enrolled into this Arm~Each cycle is of 28 days~Cohort 9.1:~SEL 20/40/60 mg PO once weekly; DEX 28/20 mg PO twice weekly; POM 4 mg PO QD Days 1-21; Elotuzumab (ELO) 10/20 mg/kg IV will be given once weekly on Days 1,8, 15 and 22 of Cycles 1-2. Starting on Cycle 3 and continuing for future cycles, elotuzumab will be dosed at 20 mg/kg on Day 1 of each cycle only.~Cohort 9.3: Selinexor, Dexamethasone, Pomalidomide and Elotuzumab will be dosed at RP2D-9.
Experimental: 10. Selinexor, Dexamethasone, and Belantamab Mafodotin (SBd)
Each cycle is of 21 days~Cohort 10.1:~SEL 40/60/80 mg PO once weekly on Days 1, 8, and 15; DEX 40 mg PO QW on Days 1, 8, and 15; Belantamab Mafodotin (BEL) 2.5 mg/kg IV infusion every 3 weeks (Q3W) Day 1 of each cycle.~Cohort 10.3:~Selinexor, Dexamethasone, and Belantamab Mafodotin will be dosed at RP2D-10.
Experimental: 11. Selinexor, Dexamethasone, Pomalidomide, and Daratumumab (SDPd)
Each Cycle is of 28 days~Cohort 11.1 SEL 40/60 mg PO once weekly on Days 1, 8, and 15; DEX total 40 mg weekly (IV or PO) single or divided doses on Days 1, 8, 15, and 22; POM 4 mg PO QW Days 1-21; DARA 16 mg/kg IV or SC QW on Days 1, 8, 15 and 22 of Cycles 1-2 and on Days 1 and 15 of Cycles 3-6, Day 1 of every Cycle greater than (>6).~Cohort 11.3 Selinexor, Dexamethasone, Pomalidomide, and Daratumumab will be dosed at RP2D-11.
Sponsors
Leads: Karyopharm Therapeutics Inc

This content was sourced from clinicaltrials.gov

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