Selinexor for Myelofibrosis
(SENTRY-2 Trial)
Recruiting in Palo Alto (17 mi)
+47 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Karyopharm Therapeutics Inc
Disqualifiers: Pregnancy, Heart disease, Stroke, others
No Placebo Group
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?The main purpose of this study with corresponding optional expansion is to evaluate the efficacy of selinexor in JAKi-naïve participants with myelofibrosis (MF) and moderate thrombocytopenia based on spleen volume reduction (SVR). Additional efficacy and safety parameters will also be assessed during the study.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug Selinexor for treating myelofibrosis?
The research mentions Selinexor as a selective inhibitor of nuclear transport, which is being explored as a novel therapy for myelofibrosis, suggesting it targets different pathways than current treatments. However, specific effectiveness data for Selinexor in myelofibrosis is not provided in the available research.
12345Is Selinexor safe for human use?
The research discusses Selinexor as a selective inhibitor of nuclear transport, but it does not provide specific safety data for its use in humans. Therefore, no relevant safety information is available from the provided research articles.
16789How is the drug Selinexor unique in treating myelofibrosis?
Selinexor is unique because it targets a different pathway than the commonly used JAK inhibitors. It works as a selective inhibitor of nuclear transport, which is a novel approach for treating myelofibrosis, potentially offering benefits for patients who cannot tolerate JAK inhibitors.
1351011Eligibility Criteria
This trial is for individuals with myelofibrosis who haven't been treated with JAK inhibitors and have moderate thrombocytopenia. They should have symptoms of myelofibrosis, measurable spleen enlargement, specific risk categories per DIPSS, an ECOG Performance Status of 2 or less, certain blood cell counts without transfusions or growth factors recently, and adequate liver function.Inclusion Criteria
My spleen is enlarged, measuring over 450 cm^3 on a recent scan.
I am able to care for myself and up and about more than 50% of my waking hours.
My platelet count is between 50 and 100, without recent transfusions.
+9 more
Exclusion Criteria
More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase)
I have been treated with JAK inhibitors for myelofibrosis.
I can't tolerate two different anti-nausea medications for the first two treatment cycles.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive selinexor 40 mg or 60 mg oral tablets once weekly in 28-day cycles, with optional add-on medication based on spleen volume reduction (SVR) values
Until progression or intolerable toxicity
Follow-up
Participants are monitored for safety and effectiveness after treatment
48 months
Optional Expansion
Participants may receive additional treatment with selinexor and optional add-on medication based on SVR values
Participant Groups
The study tests the effectiveness of Selinexor in reducing spleen volume in patients new to JAK inhibitor treatment for myelofibrosis with low platelet counts. It will compare different doses (40 mg and 60 mg) against other treatments like Pacritinib and Momelotinib.
4Treatment groups
Experimental Treatment
Group I: Selinexor 60 mg (Optional Expansion Arm)Experimental Treatment4 Interventions
Participants will receive selinexor 60 mg oral tablets QW (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first. Optional add-on medication (ruxolitinib \[5 mg or 10 mg twice daily\], pacritinib \[200 mg twice daily\], or momelotinib \[200 mg once daily\]) may be initiated for participants whose SVR is less than (\<) 10% at Week 12 or \<35% at Week 24 based on the participants platelet count values (i.e., ruxolitinib if platelets greater than or equal to \[\>=\] 50 x 10\^9/L, pacritinib if platelets \<50 x 10\^9/L, momelotinib if platelets is \>=50 x 10\^9/L and hemoglobin level is \< 10 gram per deciliter \[g/dL\]).
Group II: Selinexor 60 mg (Arm 1)Experimental Treatment4 Interventions
Participants will receive selinexor 60 milligrams (mg) oral tablets once weekly (QW) (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first and followed by optional add-on medication dosing may be initiated based on Spleen Volume Reduction (SVR) values.
Group III: Selinexor 40 mg (Optional Expansion Arm)Experimental Treatment4 Interventions
Participants will receive selinexor 40 mg oral tablets QW (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first. Optional add-on medication (ruxolitinib \[5 mg or 10 mg twice daily\], pacritinib \[200 mg twice daily\], or momelotinib \[200 mg once daily\]) may be initiated for participants whose SVR is \<10% at Week 12 or \<35% at Week 24 based on the participants platelet count values (i.e., ruxolitinib if platelets \>= 50 x 10\^9/L, pacritinib if platelets \<50 x 10\^9/L, momelotinib if platelets is \>=50 x 10\^9/L and hemoglobin level is \< 10 g/dL).
Group IV: Selinexor 40 mg (Arm 2)Experimental Treatment4 Interventions
Participants will receive selinexor 40 mg oral tablets QW (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first and followed by optional add-on medication dosing may be initiated based on SVR values.
Selinexor is already approved in United States, Canada for the following indications:
🇺🇸 Approved in United States as Xpovio for:
- Multiple myeloma
- Diffuse large B-cell lymphoma
🇨🇦 Approved in Canada as Xpovio for:
- Multiple myeloma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Duke UniversityDurham, NC
Huntsman Cancer InstituteSalt Lake City, UT
City of Hope - Duarte Main SiteDuarte, CA
Maryland Oncology Hematology - Independent of SCRI/ US OncologyColumbia, MD
More Trial Locations
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Who Is Running the Clinical Trial?
Karyopharm Therapeutics IncLead Sponsor
References
Novel treatments for myelofibrosis: beyond JAK inhibitors. [2022]Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Given the central role of the JAK-STAT pathway in the pathobiology of myelofibrosis, JAK inhibitors are the mainstay of current pharmacologic management. Although these therapies have produced meaningful improvements in splenomegaly and symptom burden, JAK inhibitors do not significantly impact disease progression. In addition, many patients are ineligible because of disease-related cytopenias, which are exacerbated by JAK inhibitors. Therefore, there is a continued effort to identify targets outside the JAK-STAT pathway. In this review, we discuss novel therapies in development for myelofibrosis. We focus on the preclinical rationale, efficacy and safety data for non-JAK inhibitor therapies that have published or presented clinical data. Specifically, we discuss agents that target epigenetic modification (pelabresib, bomedemstat), apoptosis (navitoclax, navtemdalin), signaling pathways (parsaclisib), bone marrow fibrosis (AVID200, PRM-151), in addition to other targets including telomerase (imetelstat), selective inhibitor of nuclear transport (selinexor), CD123 (tagraxofusp) and erythroid maturation (luspatercept). We end by providing commentary on the ongoing and future therapeutic development in myelofibrosis.
Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study. [2022]Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin
Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms. [2022]Ruxolitinib is the front-line non-palliative treatment for myelofibrosis (MF). However, a significant number of patients lose or present suboptimal response, are resistant or have unacceptable toxicity. In an attempt to improve response and avoid the adverse effects of this drug, we evaluated the combination of 17 drugs with ruxolitinib in ex vivo models of peripheral blood mononuclear cells from MF patients and cell lines. We found that the combination ruxolitinib and nilotinib had a synergistic effect against MF cells (ΔEC50 nilotinib, -21.6%). Moreover, the addition of prednisone to combined ruxolitinib/nilotinib improved the synergistic effect in all MF samples studied. We evaluated the molecular mechanisms of combined ruxolitinib/nilotinib/prednisone and observed inhibition of JAK/STAT (STAT5, 69.2+11.8% inhibition) and MAPK (ERK, 29.4+4.5% inhibition) signaling pathways. Furthermore, we found that the triple therapy combination inhibited collagen protein and COL1A1 gene expression in human bone marrow mesenchymal cells. Taken together, we provide evidence that combined ruxolitinib/nilotinib/prednisone is a potential therapy for MF, possibly through the anti-fibrotic effect of nilotinib, the immunomodulatory effect of ruxolitinib and prednisone, and the anti-proliferative effect of ruxolitinib. This combination will be further investigated in a phase Ib/II clinical trial in MF.
Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVR35) and reduced symptoms in patients with myelofibrosis no longer benefiting from ruxolitinib. Here, we report the exploratory post-hoc biomarker analyses from cohort 1a.
Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients. [2023]Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes arising from fibrotic changes in the bone marrow. While the JAK2 inhibitor ruxolitinib provides some clinical benefit, there remains a substantial unmet need for novel targeted therapies to better modify the disease process or eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting Jak2 mutation-driven malignancies. CBL0137 is a drug derived from curaxin targeting the Facilitates Chromatin Transcription (FACT) complex. It is reported to trap the FACT complex on chromatin thereby activating p53 and inhibiting NF-kB activity. We therefore assessed the activity of CBL0137 in primary patient samples and murine models of Jak2-mutated MPN and found it preferentially targets CD34+ stem and progenitor cells from myelofibrosis patients by comparison with healthy control cells. Further we investigate its mechanism of action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.
Ruxolitinib for the treatment of primary myelofibrosis. [2021]The pharmacology, pharmacokinetics, pharmacogenomics, clinical efficacy, and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed.
U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. [2022]On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.), an inhibitor of the Janus kinases 1 and 2, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (study 1) or best available therapy (study 2). The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of ≥ 35% at 24 weeks (study 1) or 48 weeks (study 2). The key secondary endpoint in study 1 was the proportion of patients who experienced a ≥ 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks. The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P
Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. [2021]Ruxolitinib, an oral JAK1 and JAK2 inhibitor, is approved in the US for patients with intermediate or high-risk myelofibrosis (MF), a chronic neoplasm associated with aberrant myeloproliferation, progressive bone marrow fibrosis, splenomegaly, and burdensome symptoms. Phase III clinical studies have shown that ruxolitinib reduces splenomegaly and alleviates MF-related symptoms, with concomitant improvements in quality of life measures, for the overwhelming majority of treated patients. In addition, ruxolitinib provided an overall survival advantage as compared with either placebo or what was previously considered best available therapy in the two phase III studies. The most common adverse events with ruxolitinib treatment include dose-dependent anemia and thrombocytopenia, which are expected based on its mechanism of action. Experience from the phase III studies shows that these hematologic events can be managed effectively with dose modifications, temporary treatment interruptions, as well as red blood cell transfusions in the case of anemia and, importantly, are rarely cause for permanent treatment discontinuation. This review summarizes data supporting appropriate individualized patient management through careful monitoring of blood counts and dose titration as needed in order to maximize treatment benefit.
Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor. [2021]This phase I study evaluated selective JAK2 inhibitor XL019 in 30 patients with myelofibrosis. The initial dose cohorts were 100, 200, and 300 mg orally on days 1-21 of a 28-day cycle. Central and/or peripheral neurotoxicity developed in all patients. Subsequently, patients were treated on lower doses; neurotoxicity was again observed, leading to study termination. Peripheral neuropathy resolved in 50%, and central neurotoxicity in all patients within months after therapy cessation. Myelosuppression was minimal. The terminal half-life of XL019 was approximately 21 h, with steady state reached by Day 8. International Working Group defined responses were seen in three (10%) patients.
How ruxolitinib modified the outcome in myelofibrosis: focus on overall survival, allele burden reduction and fibrosis changes. [2021]Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has shown superiority as compared to available conventional chemotherapies, in terms of reduction in splenomegaly and improvement of symptoms and quality of life. Areas covered: Data published about overall survival in the major randomized sponsored trials and in independent series of patients were detailed. Indeed, data regarding action of ruxolitinib on allele burden reduction and potential activity of the drug on pathogenetic mechanisms involved in increased fibrosis has been reviewed. Expert commentary: Data extrapolated from clinical trials demonstrated an advantage of survival when the drug was compared to placebo or to best available therapy. Moreover, in the long-term, JAK2 allele burden was reduced during treatment and about 50% of patients achieved improvement or stabilization of fibrosis. For this latter activity, several pathways have been involved. In conclusion, ruxolitinib is able to modify the natural outcome of patients affected by myelofibrosis, independently from its nature, both in primary and secondary diseases.
Fibroblast dynamics as an in vitro screening platform for anti-fibrotic drugs in primary myelofibrosis. [2022]Although the cause for bone marrow fibrosis in patients with myelofibrosis remains controversial, it has been hypothesized that it is caused by extensive fibroblast proliferation under the influence of cytokines generated by the malignant megakaryocytes. Moreover, there is no known drug therapy which could reverse the process. We studied the fibroblasts in a novel system using the hanging drop method, evaluated whether the fibroblasts obtain from patients are part of the malignant clone of not and, using this system, we screen a large library of FDA-approved drugs to identify potential drugs candidates that might be useful in the treatment of this disease, specifically which would inhibit fibroblast proliferation and the development of bone marrow fibrosis. We have found that the BM fibroblasts are not part of the malignant clone, as previously suspected and two immunosuppressive medications-cyclosporine and mycophenolate mophetil, as most potent suppressors of the fibroblast collagen production thus potentially inhibitors of bone marrow fibrosis production in myelofibrosis.