Multiple Myeloma Clinical Trial
Selinexor and Backbone Treatments of Multiple Myeloma Patients
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)
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 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 10 combination therapies in 11 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), and Arm 11 (SDPd) 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.
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).
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:
MM that does not express M-protein or FLC (i.e., non-secretory MM is excluded), and quantitative immunoglobulin levels cannot be used instead.
Documented active systemic amyloid light chain amyloidosis.
Active plasma cell leukemia.
Red Blood Cell (RBC) and platelet transfusions and blood growth factors within 14 days of C1D1.
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.
Patients with history of spinal cord compression with residual paraplegia (Dose Escalation Phase only).
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:
Symptomatic ischemia, or
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
Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3, or
Myocardial infarction (MI) within 3 months prior to C1D1
Ejection fraction (EF) < 50% at Screening
Uncontrolled active hypertension.
Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose.
Known active hepatitis A, B or C.
Known human immunodeficiency virus (HIV) infection or HIV seropositivity.
Any active gastrointestinal dysfunction that prevents the patient from swallowing tablets or interferes with absorption of study treatment.
Currently pregnant or breastfeeding.
A serious active psychiatric or active medical condition which, in the opinion of the Investigator, could interfere with treatment.
Hypersensitivity to any of the treatments for the arm in which the patient is enrolled.
SVd Arm (Arm 2), SPVd (Arm 4), and SNd Arm (Arm 8) only: Prior history of neuropathy Grade > 2, or Grade ≥ 2 neuropathy with pain at Screening (within 28 days prior to C1D1).
Patients who are eligible for the selinexor PK Run-in only: Treatment with moderate or strong inhibitors/inducers of CYP3A within 7 days prior to Day 1 of the PK Run-in period.
Patients who are eligible for the selinexor PK Run-in only: Not able to receive a strong CYP3A4 inhibitor due to concomitant medications.
SKd arm only: HBs Ag + plus HBc Ab + even though no active hepatitis B virus (HBV) hepatitis. If HBs Ag - plus HBc Ab +, treating physician needs to contact the medical monitor.
Prior exposure to a selective inhibitor of nuclear export (SINE) compound, including selinexor.
SBd (Arm 10): Only:
Current corneal epithelial disease except mild punctate keratopathy.
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There are 19 Locations for this study
Gilbert Arizona, 85234, United States
Los Angeles California, 0095, United States
Boston Massachusetts, 02114, United States
Boston Massachusetts, 02215, United States
Omaha Nebraska, 68198, United States
Hackensack New Jersey, 07601, United States
New York New York, 10032, United States
New York New York, 10065, United States
Rochester New York, , United States
Chapel Hill North Carolina, 27599, United States
Durham North Carolina, 27710, United States
Nashville Tennessee, 37203, United States
Seattle Washington, 98109, United States
Madison Wisconsin, 53792, United States
Winnipeg Manitoba, R3E 0, Canada
St. John's Newfoundland and Labrador, A1B 3, Canada
Halifax Nova Scotia, B3H 2, Canada
Toronto Ontario, M5G 2, Canada
Montreal Quebec, H1T 2, Canada
Montreal Quebec, H3A 1, Canada
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