The primary objective of this Phase Ib/II trial is to study the safety and tolerability of the combination of selinexor, carfilzomib, isatuximab-OBDS (on body delivery system) and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma, who have received at least one line of therapy. The phase Ib portion comprises the safety run-in with 6-12 patients, with the option to reduce the selinexor dose from 40 mg to 20 mg if the higher dose reaches the prescribed toxicity threshold. The Phase II portion of the trial will test the Recommended Phase 2 Dose (RP2D) in an expansion cohort of up to 50 patients.
Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
Age ≥ 18 years at the time of consent.
ECOG Performance Status of ≤2 within 28 days prior to registration. A performance status of >2 will be allowed only if it is related to bone pain that is expected to improve with treatment.
del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation
Active infection requiring systemic therapy (Note: subjects can be enrolled if they will be completing antibiotic therapy by the time of actual start date of treatment)
Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
Known additional malignancy that is active and/or progressive, requiring urgent or new treatment. Exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, prostate cancer on stable hormonal therapy, DCIS or other cancer for which the subject has been disease-free for at least three years. Patients who have undergone a curative procedure for another malignancy are eligible.
Active central nervous system (CNS) metastases. NOTE: Subjects who are symptomatic and have not undergone prior brain imaging must undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to registration to exclude brain metastases.
Sequential
Selinexor
DrugPhase I: Selinexor at assigned dose by mouth begin Day 1, 8, 15, and 22 until study treatment stop. - Dose Levels: -1: 20mg weekly 0 (Starting Dose): 40mg weekly 1: 60mg weekly Phase II: Selinexor at assigned dose by mouth based on the phase 1 findings. Selinexor will be taken weekly (Days 1, 8, 15, and 22).
Carfilzomib
DrugPhase I and Phase II: Carfilzomib IV will be administered on Day 1, 8, and 15. The first dose of carfilzomib will be carfilzomib 20mg/m2 IV. Every dose after will be carfilzomib 56mg/m2.
Isatuximab
DrugPhase I and Phase II: Isatuximab 1400mg will be administered by injection from the wearable device. For the first 28 days isatuximab will be administered on days 1, 8, 15, and 22. For every cycle after isatuximab will be administered on days 1 and 15.
Isatuximab SC Wearable Injection System
DevicePhase I and Phase II: Isatuximab 1400mg will be administered by injection from the wearable device. For the first 28 days isatuximab will be administered on days 1, 8, 15, and 22. For every cycle after isatuximab will be administered on days 1 and 15.
Dexamethasone
DrugPhase I and Phase II: Dexamethasone 40mg will be administered either by IV or orally on Days 1, 8, 15, and 22.
Adverse Events
Adverse events will be assessed by evaluating Grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Progression-free Survival (PFS)
PFS will be calculated from the date of start of study therapy to the date of progression based on International Myeloma Working Group (IMWG) criteria, or date of death due to any cause should progression not have occurred.
Overall Response Rate (ORR)
ORR will include confirmed stringent complete response (sCR), confirmed complete response (CR), confirmed very good partial response (VGPR), and confirmed partial response (PR), and will be determined as per IMWG criteria.
Minimal Residual Disease (MRD) Rate
MRD will be assessed by multiparametric flow cytometry and/or next-generation sequencing (NGS).
Progression-free Survival (PFS) in subgroup population
Comparison of PFS between patients previously exposed to anti-CD38 therapy and those naïve/exposed but not refractory to the combination of carfilzomib and daratumumab will be made by subgroup analysis.
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Natalie Callander
Lead sponsor
Hoosier Cancer Research Network
Sponsor institution
Sanofi
Collaborator
Karyopharm Therapeutics Inc
Collaborator
University of Wisconsin, Madison
Collaborator
