Multiple Myeloma
Conditions
Keywords
Selinexor, KCP-330, STOMP, Multiple Myeloma, Relapsed/Refractory, Dexamethasone, Pomalidomide, Bortezomib, Karyopharm, Lenalidomide, Daratumumab, Newly Diagnosed, Carfilzomib, Ixazomib, Elotuzumab, Clarithromycin, Belantamab mafodotin, Mezigdomide, CC-92480, BMS-986348
Brief summary
This study will independently assess the efficacy and safety of 11 combination therapies in 12 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); enrollment complete * 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); enrollment complete * Arm 5: Selinexor + dexamethasone + daratumumab (SDd); enrollment complete * Arm 6: Selinexor + dexamethasone + carfilzomib (SKd); enrollment complete * Arm 7: Selinexor + dexamethasone + lenalidomide (SRd) in NDMM; enrollment complete * Arm 8: Selinexor + dexamethasone + ixazomib (SNd); enrollment complete * Arm 9: Selinexor + dexamethasone + pomalidomide + elotuzumab (SPEd); enrollment complete * Arm 10: Selinexor + dexamethasone + belantamab mafodotin (SBd); enrollment complete * Arm 11: Selinexor + dexamethasone + pomalidomide + daratumumab (SDPd); enrollment complete * Arm 12: Selinexor + dexamethasone + mezigdomide (SMd); actively recruiting 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. This run-in period does not apply to Arm 12 (SMd).
Detailed description
This is a multi-center, open-label, clinical study with Dose Escalation (Phase 1) and Expansion (Phase 2) to independently assess the MTD, efficacy , and safety of 11 combination therapies in 12 arms in patients with RRMM and NDMM. Patients will be assigned to treatment arms based on their diagnoses and treatment histories. For 9 patients, a PK Run-in period will precede Cycle 1 (DLT evaluation) to assess selinexor PK when co-administered with a strong CYP3A4 inhibitor. In the Dose Escalation Phase (Phase 1): (a) in Arm 1 (SPd), Arm 2 (SVd), and Arm 3 (SRd in RRMM), patients will be randomized to either QW or BIW selinexor dosing cohorts; (b) in Arm 5 (SDd), patients will be sequentially assigned in blocks of 3 to either QW or BIW selinexor dosing; (c) in Arm 4 (SPVd), Arm 6 (SKd), Arm 7 (Srd in NDMM), Arm 8 (SNd), Arm 9 (SPEd), Arm 10 (SBd), Arm 11 (SDPd), and Arm 12 (SMd) patients will be assigned to QW selinexor dosing. Cohort 1.4 is included from Version 10 to study safety and tolerability of SPd with selinexor 40 mg QW, is lower than RP2D (ie, selinexor 60 mg QW) in combination with pomalidomide 4 mg. Cohort 1.4 is a different expansion cohort from the one with RP2D (ie, Cohort 1.3). In Cohort 1.4, 20 patients will be enrolled in total. Starting in protocol Version 8.0, patients enrolled to the Dose Escalation Phase of Arm 4 (SPVd), Arm 6 (SKd), Arm 8 (SNd), Arm 9 (SPEd), Arm 10 (SBd), and Arm 11 (SDPd) will first be enrolled to a 14-day PK Run-in period (selinexor +/- clarithromycin) until 9 patients have been enrolled. During this 14-day PK Run-in period, selinexor 40 milligrams (mg) will be administered alone on Day 1, clarithromycin 500 mg twice daily (BID) will be administered on Days 2-8, and selinexor 40 mg will again be administered on Day 8 with the morning clarithromycin dose. Blood samples for PK analysis will be collected pre-dose and 1 (± 10 min), 1.5 (± 10 min), 2 (± 10 min), 3 (± 10 min), 4 (± 10 min), 5 (± 10 min), 6 (± 10 min), 8 (± 10 min), and 24 h (± 30 min) hours after selinexor is dosed on Day 1 (without clarithromycin) and Day 8 (with clarithromycin). Patients will then proceed to the DLT evaluation period that will begin after the completion of the 14-day PK Run-in period; this day will be designated as Cycle 1 Day 1 (C1D1) in the Dose Escalation Phase. Starting in protocol v12, in Arm 12 (SMd) additional PK sampling for mezigdomide will be collected concurrently with selinexor on Cycle 1 Day 1 (C1D1) at 2,4, and 6 hrs post-mezigdomide/selinexor dose; additional mezigdomide PK samples will be collected pre-mezigdomide dose on Days 8 and 15 of Cycles 1 and 2.
Interventions
DRUGSelinexor
Oral tablets
DRUGDexamethasone
Oral tablets
DRUGLenalidomide
Oral capsule
DRUGPomalidomide
Oral tablets
DRUGBortezomib
Subcutaneous Injection (single use vial)
DRUGDaratumumab
Intravenous Infusion
DRUGCarfilzomib
Intravenous infusion
DRUGIxazomib
Oral capsule
DRUGElotuzumab
Intravenous infusion
DRUGClarithromycin
Tablets
DRUGBelantamab Mafodotin
Intravenous infusion
DRUGMezigdomide
Oral Capsules
Sponsors
Bristol-Myers Squibb
Karyopharm Therapeutics Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent signed in accordance with federal, local, and institutional guidelines. 2. Age greater than or equal to (≥) 18 years at the time of informed consent. 3. Histologically confirmed diagnosis with measurable disease for relapsed/refractory myeloma. 4. Symptomatic MM, based on IMWG guidelines. 5. Patients must have measurable disease as defined by at least one of the following: 1. Serum M-protein ≥ 0.5 gram per deciliter (g/dL) by serum protein electrophoresis (SPEP) or, for immunoglobulin A (IgA) myeloma, by quantitative IgA 2. Urinary M-protein excretion at least 200 mg/24 hours 3. Serum free light chain (FLC) ≥ 100 milligram per liter (mg/L), provided that FLC ratio is abnormal 4. 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 6. 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. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. 8. 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 and SMd: 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 9. Adequate renal function within 28 days prior to C1D1. For Arms 1-11, 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, SBd, and SMd arms * ≥ 45 mL/min for SPd, SPVd, SPEd and SDPd arms * \> 60 mL/min for SRd arm 10. Adequate hematopoietic function within 28 days prior to C1D1: 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. * SMd (Arm 12) only: platelet count ≥75,000 for subjects in whom \<50% of bone marrow nucleated cells are plasma cells; or platelet count \<50,000 for subjects in whom ≥50% of bone marrow nucleated cells are plasma cells. 11. 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 90 days following the last dose of study treatment. For Arm 12 (SMd), all study subjects must agree and adhere to all testing and contraception requirements as specified in the mezigdomide Global Pregnancy Prevention Plan (PPP) SPd (Arm 1) Only. 12. Relapsed or refractory MM with: 1. 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) 2. ≤ 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) 3. Previously undergone ≥ 2 cycles of lenalidomide and a PI (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: 13. 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: 14. 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: 15. 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: 16. 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. 17. 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: 18. Patients may have received prior PIs; however, their MM must NOT be refractory to carfilzomib. SRd in NDMM (Arm 7) Only: 19. 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: 20. 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: 21. 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: 22. 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: 23. 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). SMd (Arm 12) only: 24. Patients with RRMM who have received at least 2 prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody. Patients must have either failed a T-cell redirecting treatment (eg, CAR-T or bispecific antibody) or otherwise cannot receive such therapy due to either medical or logistic reasons.
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 (Dose-escalation): Maximum Tolerated Dose (MTD) | 12 months | MTD for once weekly and twice weekly selinexor dose cohorts in the 11 Arms will be evaluated. |
| Phase 1 (Dose-escalation): Recommended Phase-2 dose (RP2D) | 12 months | RP2D for each Arm will be determined. |
| Phase 1 (Dose-escalation): Maximum Plasma Concentration (Cmax) of Selinexor | Pre-dose, 1 hour, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post-dose on Day 1 (without clarithromycin) and Day 8 (with clarithromycin) | Cmax of selinexor over a dosing interval when given with and without clarithromycin. |
| Phase 1 (Dose-escalation): Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Selinexor | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post-dose on Day 1 (without clarithromycin) and Day 8 (with clarithromycin) | Total exposure of selinexor in the blood (AUC0-last) from the time of dosing to the last measurable concentration collected when given with and without clarithromycin. |
| Phase 1 (Dose-escalation): Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated) (AUC0-inf) | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post-dose on Day 1 (without clarithromycin) and Day 8 (with clarithromycin) | — |
| Phase 2 (Expansion): Overall response rate (ORR) | 12 months | ORR for each Arm independently. ORR to include stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), according to the International Myeloma Working Group (IMWG) criteria. |
| Phase 2 (Expansion): Duration of response (DOR) | 12 months | Duration of response for each Arm. DOR is defined as the number of days from the date of the first evidence of objective response until progression. |
| Phase 2 (Expansion): Clinical Benefit Rate (CBR) | 12 months | CBR is defined the point estimate of the percentage of patients in that arm who have a response of sCR, CR, VGPR, PR or Minimal response (MR), as assessed by IMWG criteria. |
Countries
Canada, United States
Contacts
Primary ContactKaryopharm Medical Information
Outcome results
None listed