Selinexor + Carfilzomib + Dexamethasone for Multiple Myeloma
(SINE Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Chicago
Must not be taking: Anticancer therapy, Antivirals
Disqualifiers: Pregnancy, Heart failure, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This phase I trial studies the side effects and best dose of selinexor and carfilzomib when given together with dexamethasone in treating patients with multiple myeloma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as selinexor and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving selinexor, carfilzomib, and dexamethasone may be a better treatment for multiple myeloma.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had radiation, chemotherapy, or immunotherapy within 2 weeks before starting the trial, and you cannot be on other anticancer therapies during the trial.
What data supports the effectiveness of the drug combination Selinexor, Carfilzomib, and Dexamethasone for treating multiple myeloma?
Research shows that the combination of Selinexor, Carfilzomib, and Dexamethasone can help control disease in patients with relapsed or refractory multiple myeloma, including those who are resistant to Carfilzomib. In a study, 71% of patients had at least a minimal response, and the median overall survival was 22.4 months.
12345What makes the drug combination of Selinexor, Carfilzomib, and Dexamethasone unique for treating multiple myeloma?
This drug combination is unique because it includes Selinexor, which works by blocking a protein that helps cancer cells grow, making it different from other treatments that primarily target the cancer cells directly. This combination is used for patients with relapsed or refractory multiple myeloma, offering a novel approach by combining different mechanisms of action to tackle the disease.
678910Eligibility Criteria
Adults with relapsed or refractory multiple myeloma, who have tried at least two prior therapies including a proteasome inhibitor and a cereblon-binding agent. They must have measurable disease, be able to follow the study schedule, and use effective contraception if of childbearing potential. Excluded are those with recent major surgery, known allergies to certain drug components, serious medical conditions that could interfere with treatment, previous Selinexor exposure, unstable heart conditions, active infections like HIV or hepatitis B/C.Inclusion Criteria
Your bilirubin level is not too high, unless you have Gilbert's syndrome, in which case it can be a little higher.
Written informed consent in accordance with federal, local, and institutional guidelines
I have a measurable plasmacytoma that needs PI review before I join.
+20 more
Exclusion Criteria
I am HIV positive.
I am allergic or cannot tolerate certain medications, including blood thinners, antiviral drugs, or fluids due to heart or lung problems.
I haven't had any bleeding issues or coagulation problems in the last month.
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive selinexor, carfilzomib, and dexamethasone. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
28 days per course
Follow-up
Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days and then every 3 months for 2 years.
2 years
Participant Groups
The trial is testing the combination of selinexor and carfilzomib with dexamethasone to find the best dose and side effects for treating multiple myeloma that has returned after treatment or is not responding. Selinexor and dexamethasone are chemotherapy drugs while carfilzomib blocks enzymes needed for cancer cell growth.
1Treatment groups
Experimental Treatment
Group I: Selinexor, carfilzomib, dexamethasoneExperimental Treatment3 Interventions
Patients receive selinexor PO, carfilzomib IV, and dexamethasone PO QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Carfilzomib is already approved in United States, European Union, Canada, Japan for the following indications:
🇺🇸 Approved in United States as Kyprolis for:
- Multiple myeloma
🇪🇺 Approved in European Union as Kyprolis for:
- Multiple myeloma
🇨🇦 Approved in Canada as Kyprolis for:
- Multiple myeloma
🇯🇵 Approved in Japan as Kyprolis for:
- Multiple myeloma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of ChicagoChicago, IL
Mayo Clinic (AZ)Scottsdale, AZ
University of Michigan Comprehensive Cancer CenterAnn Arbor, MI
Wayne State University Karmanos Cancer InstituteDetroit, MI
More Trial Locations
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Who Is Running the Clinical Trial?
University of ChicagoLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. [2023]Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665).
Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. [2023]Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1. Selinexor (KPT-330) is the first-in-human SINE compound. Early phase clinical trials have established the safety profile of this agent and have shown promising efficacy in combination with low-dose dexamethasone and other anti-MM agents. The combination of selinexor and dexamethasone has demonstrated activity in "penta-refractory" MM, (ie, MM refractory to the 5 most active anti-MM agents currently used in treatment). We have reviewed the available data on the molecular implications of XPO1 inhibition in MM. We also reviewed the pertinent early phase clinical data with SINE compounds and discuss management strategies for common toxicities encountered with use of selinexor.
Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. [2023]Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.
Selinexor-Bortezomib-Dexamethasone: A Review in Previously Treated Multiple Myeloma. [2023]Selinexor [Nexpovio® (EU); Xpovio® (USA)] is a first-in-class, selective exportin-1 inhibitor. Oral selinexor once weekly in combination with subcutaneous bortezomib once weekly and oral dexamethasone twice weekly (selinexor-bortezomib-dexamethasone) is approved in the EU and USA for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. In the open-label, randomized, phase 3 BOSTON trial, this regimen significantly prolonged progression-free survival (PFS) compared with the standard bortezomib-dexamethasone regimen in patients with previously treated multiple myeloma. Selinexor-bortezomib-dexamethasone had a generally manageable tolerability profile and an acceptable safety profile in BOSTON, with a lower incidence of peripheral neuropathy (a bortezomib-induced toxicity) compared with bortezomib-dexamethasone. The triplet regimen uses less bortezomib and dexamethasone during the first 24 weeks of treatment. The efficacy and safety profiles of selinexor-bortezomib-dexamethasone, combined with its once-weekly administration of selinexor and bortezomib, make it a useful additional triplet therapy option for previously treated multiple myeloma.
Real World Efficacy and Toxicity of Selinexor: Importance of Patient Characteristics, Dose Intensity and Post Progression Outcomes. [2023]Selinexor is an orally available selective inhibitor of exportin-1 that has offered a new treatment option in relapsed or refractory myeloma (RRMM) either in combination with dexamethasone (Sd) or with bortezomib and dexamethasone (SVd).
Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma. [2018]The goal of this retrospective study was to compare the efficacy and toxicity of lenalidomide-dexamethasone (len/dex) vs. melphalan-prednisone-lenalidomide (MPR) as upfront therapy for newly diagnosed elderly patients with myeloma.
Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil). [2022]To evaluate the safety of the methotrexate (MTX)-leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease-modifying antirheumatic drugs (DMARDs) or Janus kinase inhibitors (JAKi).
Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. [2019]Mycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimus (Prograf) as well in renal transplant patients, there is a lack of pharmacokinetic studies clarifying drug interactions between the three agents. A pharmacokinetic study was performed on 18 stable renal transplant patients receiving MMF and tacrolimus together, and four control groups, one receiving tacrolimus alone, two receiving CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion (Neoral). Area-under-the-curve values were calculated for each drug to assess if there was a reciprocal effect on the respective bioavailability of each. In vitro, the immunosuppressive effect of trough level plasma from each patient group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions spiked with various combinations of each drug. There was a minimal effect of MMF on tacrolimus pharmacokinetics. However, patients receiving tacrolimus and MMF displayed significantly higher levels (Cmin and area under the curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmune or Neoral) and the same dose of MMF (50.2 +/- 16.5 vs 32.1 +/- 16.7 micrograms h/ml AUC, p
Leflunomide and malononitrilamides. [2021]Leflunomide is a new immunomodulatory drug that is effective in experimental models of autoimmune diseases and in allo or xenotransplantation. In a phase II clinical trial, leflunomide showed high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite A77 1726, which is a malononitrilamide. The in vitro and in vivo mechanisms of action of this class of compounds are not defined completely. Several malononitrilamide analogues and A77 1726 inhibit T- and B-cell proliferation, suppress immunoglobulin production, and interfere with cell adhesion. Although no central molecular mechanism of action has been proposed to explain all the effects of the malononitrilamides, the inhibition of de novo pyrimidine biosynthesis and of cytokine- and growth factor receptor-associated tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell proliferation and function. Leflunomide is effective when administered in daily dosages of 10 mg and 25 mg to patients with active rheumatoid arthritis. The improved efficacy of a 25 mg dose is associated with a higher incidence of adverse effects (gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia). Because of the long plasma half-life of A77 1726 (11 to 16 days), loading doses are necessary to achieve steady state concentrations. Phase III randomized, placebo-controlled trials that use daily dosages of 10 mg or 20 mg are under way in the United States and Europe to confirm and extend the results of the phase II study. Malononitrilamide analogues of A77 1726 are being evaluated for immunosuppressive efficacy in preclinical models of transplantation. If these analogues show efficacies and therapeutic indexes that are similar to leflunomide in these models and that have shorter half-lives than A77 1726 in phase I trials, the preclinical and phase I data will be used to select the analogues for phase II trials in organ transplant recipients.
Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study. [2023]We investigate safety and efficacy in common clinical practice of the combination of carfilzomib and dexamethasone (Kd56) approved for the ENDEAVOR trial for the treatment of relapsed or refractory multiple myeloma.