NCT07200102Phase 1Recruiting
Washington University School of Medicine · Washington University School of Medicine, St Louis, Missouri
The outcomes in patients with relapsed multiple myeloma refractory to triple-therapy (anti-CD38, immunomodulatory drugs (IMiD) and proteasome inhibitors (PI)) remain poor. These patients are eligible for chimeric antigen receptor T-cells (CAR-T), which rely on redirecting autologous T-cells to clear myeloma cells by targeting B-cell maturation antigen (BCMA). BCMA CAR-T therapy is not curative, and unlike autologous stem cell transplant, there is currently no standard for maintenance therapy post CAR-T which could potentially increase MRD rates and extend progression-free survival.
Selinexor is an exportin (XPO1) inhibitor with direct anti-tumor effect used often as an adjunct with other agents as bridging therapy prior to CAR-T. As selinexor does not affect T-cell yields or fitness, T-cell collection on selinexor for CAR-T manufacturing is safe.
The aim of this study is to evaluate the safety and toxicity of selinexor in triple-exposed or refractory multiple myeloma patients with high-risk features (adverse risk cytogenetics, less than complete response (CR) post CAR-T, or extramedullary disease) following BCMA CAR-T therapy. The investigators hypothesize that selinexor as maintenance therapy following CAR-T has the potential to act synergistically with CAR-T cells leading to more durable responses.
Eligibility: 18 Years to · All · * Diagnosis of triple-class exposed or refractory multiple myeloma (MM). Diagnosis must be histologically confirmed. Patients with multiple myeloma with local amyloid deposition in the bone marrow are eligible. Only the following risk categories will be enrolled:
* High risk myeloma, defined by the presence of at least one of the following features:
* Deletion 17p and/or TP53 alteration:
* Deletion of 17p with a cancer clonal fraction (CCF) ≥20%, assessed on CD138-positive/purified plasma cells, AND/OR
* TP53 mutation identified using a validated next-generation sequencing (NGS)-based assay.
* High-risk IgH translocation with chromosome 1 abnormality:
* Presence of t(4;14), t(14;16), or t(14;20) in combination with either gain/amplification of 1q (1q+) and/or deletion of 1p32.
* Chromosome 1p32 deletion patterns:
* Monoallelic deletion of 1p32 occurring with gain/amplification of 1q, OR
* Biallelic deletion of 1p32.
* Elevated β2-microglobulin without renal dysfunction:
* Serum β2-microglobulin ≥5.5 mg/L in the setting of normal renal function, defined as serum creatinine \<1.2 mg/dL.
* Presence of extramedullary disease prior to receiving CAR-T OR
* Standard risk myeloma with MRD-positive (MRD+) disease at MRD draw around Day 58-60 post CAR-T.
* Received standard of care ciltacabtagene autoleucel (cilta-cel; Carvykti).
* Able to monitor disease response by ClonoSEQ MRD testing.
* At least 18 years of age.
* ECOG performance status ≤ 2.
* Adequate bone marrow and organ function as defined below:
* Absolute neutrophil count ≥ 1.0 K/cumm
* Platelets ≥ 50 K/cumm
* Hemoglobin ≥ 8.5 g/dL without blood transfusion within 7 days before C1D1.
* Total bilirubin ≤ 1.5 x IULN; patients with Gilbert's syndrome must have a total bilirubin \< 3 x IULN.
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
* Calculated creatinine clearance ≥ 15 mL/min by Cockcroft-Gault
* The effects of selinexor on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to C1D1 of selinexor, for the duration of study participation, and for 90 days after completion of selinexor. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
* Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
NCT04661137Phase 2Recruiting
Hackensack Meridian Health · Lombardi Comprehensive Cancer Center, Washington D.C., District of Columbia
This is a prospective, 2-arm (with an additional exploratory arm), open-label, multicenter study looking at the response rate of patients receiving selinexor (KPT-330), in combination with carfilzomib, daratumumab or pomalidomide.
Multiple Myeloma patients with documented disease progression or refractory disease while on current treatment with any carfilzomib-containing regimen (arm 1), any pomalidomide-containing regimen (arm 2) or any daratumumab-containing regimen (exploratory arm) will be included in the study. Patients will be assigned to the respective groups according to their current treatment. If a subject has received more than one of the above therapies, then assignment will be made at their physician's discretion (e.g treatment decision can be made based upon patient and physician preferred tolerance.).
Patients will receive treatment until progressive disease (PD), death, toxicity that cannot be managed by standard of care, or withdrawal, whichever occurs first.
Eligibility: 18 Years to · All · 1. Age ≥18 years at time of informed consent.
2. Histologically confirmed MM and evidence of disease progression while on one of the below MM regimens:
* Arm 1: Refractory to or disease progression while on a carfilzomib-containing regimen
* Arm 2: Refractory to or disease progression while on a pomalidomide-containing regimen
* Exploratory Arm: Refractory to or disease progression while on a daratumumab-containing regimen
3. Measurable disease as defined: Serum M-protein ≥ 0.5 g/dL; urine M-protein excretion at least 200 mg/24h; serum FLC ≥ 100 mg/L, provided that FLC is abnormal; if serum protein electrophoresis is felt to be unreliable for routine M-protein measurement (i.e. IgA MM) then quantitative Ig levels by nephelometry or turbidometry are acceptable; for non-secretory disease, bone marrow plasma cells ≥ 20% or a biopsy-proven target lesion by PET/CT or MRI is acceptable
4. Documented evidence of disease progression (by IMWG criteria) or refractory disease on the current treatment as defined as:
* Achieving SD or less for ≥ 1 cycle during treatment with regimens stated in #2 (i.e. relapsed) OR
* \<25% response (i.e. never achieved MR) or PD during or within 60 days from the end-of most recent MM regimen as listed in #2 (i.e. refractory).
5. Any non-hematological toxicities (except for peripheral neuropathy) that patients experienced from treatments in previous regimens have resolved to Grade 2 or less by Cycle 1 Day 1.
6. ECOG 2 or less
7. Adequate hepatic function within 28 days prior to C1D1:
1. Total bilirubin \< 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of \< 3 × ULN), and
2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to \<2 × ULN.
8. Adequate renal function within 28 days prior to C1D1 as determined by estimated creatinine clearance of ≥ 30 mL/min, calculated using the Cockcroft and Gault formula (140 - Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female (Cockcroft 1976).
9. Adequate hematopoietic function within 7 days prior to C1D1: total white blood cell (WBC) count ≥1500/mm3, absolute neutrophil count ≥1000/mm3, hemoglobin ≥8.5 g/dL and platelet count ≥75,000/mm3 (patients for whom \<50% of bone marrow nucleated cells are plasma cells) or ≥50,000/mm3 (patients for whom ≥50% of bone marrow nucleated cells are plasma cells).
1. Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study.
2. Patients must have:
* At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the Screening hemoglobin assessment, and
* At least a 1-week interval from the last platelet transfusion prior to the Screening platelet assessment.
However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study.
10. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.
