Selinexor for Myelofibrosis

(SENTRY-2 Trial)

Recruiting at 47 trial locations

Overseen By Karyopharm Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Karyopharm Therapeutics Inc

Disqualifiers: Pregnancy, Heart disease, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Until progression or intolerable toxicity

118 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 6 7 8 9}

How 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. ^{1 3 5 10 11}

Eligibility 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.

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.

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

Treatment Details

Interventions

• Selinexor

Trial Overview 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.

Participant Groups

Group I: Selinexor 60 mg (Optional Expansion Arm) Experimental Treatment 4 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 Treatment 4 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 Treatment 4 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 Treatment 4 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

Who Is Running the Clinical Trial?

Karyopharm Therapeutics Inc

Lead Sponsor

Trials

89

Recruited

7,200+

Richard Paulson

Karyopharm Therapeutics Inc

Chief Executive Officer since 2021

MBA from the University of Toronto's Rotman School of Management

Reshma Rangwala

Karyopharm Therapeutics Inc

Chief Medical Officer since 2023

MD, PhD

Findings from Research

JAK inhibitors are the primary treatment for myelofibrosis, effectively reducing symptoms and spleen size, but they do not significantly alter disease progression and can worsen blood cell counts in some patients.

Research is ongoing for new therapies targeting different mechanisms, such as epigenetic modification and apoptosis, which may offer alternatives for patients who cannot tolerate JAK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel treatments for myelofibrosis: beyond JAK inhibitors. Tremblay, D., Mesa, R.[2022]

In the REALISE phase 2 study involving 51 anemic myelofibrosis patients, a novel dosing strategy of ruxolitinib led to a 70% reduction in spleen size, indicating its efficacy in managing splenomegaly associated with the condition.

Despite concerns about anemia, the study found that ruxolitinib did not worsen hemoglobin levels or increase transfusion needs, suggesting it can be safely administered even in patients with anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study. Cervantes, F., Ross, DM., Radinoff, A., et al.[2022]

The combination of ruxolitinib and nilotinib showed a synergistic effect against myelofibrosis (MF) cells, with a significant reduction in drug concentration needed to achieve efficacy, indicating a promising new treatment strategy.

Adding prednisone to the ruxolitinib/nilotinib combination further enhanced its effectiveness by inhibiting key signaling pathways involved in MF, suggesting a multi-faceted approach to therapy that targets both proliferation and fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms. Cortés, AA., Diaz, RA., Hernández-Campo, P., et al.[2022]

In a phase 2 trial involving 34 patients with myelofibrosis who were not responding well to ruxolitinib, the addition of navitoclax led to a significant reduction in spleen volume and improved symptoms, indicating its efficacy as a combination treatment.

Patients showing improvements in bone marrow fibrosis or a reduction in variant allele frequency had better overall survival, suggesting that navitoclax may modify the disease progression in myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. Pemmaraju, N., Garcia, JS., Potluri, J., et al.[2022]

CBL0137, a drug derived from curaxin, shows promise in targeting Jak2 mutation-driven myelofibrosis by preferentially affecting CD34+ stem and progenitor cells from patients, indicating its potential as a novel therapy.

In murine models of myeloproliferative neoplasms, CBL0137 effectively reduced splenomegaly and reticulocyte counts, suggesting it may help alleviate some symptoms associated with myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients. Pearson, S., Blance, R., Yan, F., et al.[2023]

Ruxolitinib is an effective oral treatment for intermediate- or high-risk myelofibrosis, targeting JAK1 and JAK2 to reduce spleen size and improve symptoms, as demonstrated in Phase III trials with significant improvements in quality of life and overall survival.

The treatment has a manageable safety profile, with common side effects including anemia and thrombocytopenia, and requires dosage adjustments based on platelet counts, allowing for personalized patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. Swaim, SJ.[2021]

Ruxolitinib, the first FDA-approved treatment for myelofibrosis, significantly reduced spleen volume by ≥ 35% in 42% of patients compared to only 1% in the placebo group, demonstrating its efficacy in treating this condition.

While ruxolitinib effectively improved symptoms and spleen size, it was associated with increased risks of severe anemia, thrombocytopenia, and neutropenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Deisseroth, A., Kaminskas, E., Grillo, J., et al.[2022]

Ruxolitinib is an effective treatment for intermediate or high-risk myelofibrosis, significantly reducing spleen size and alleviating related symptoms, which improves patients' quality of life.

While ruxolitinib can cause dose-dependent anemia and thrombocytopenia, these side effects can be managed with dose adjustments and monitoring, allowing most patients to continue treatment without permanent discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. Mesa, RA., Cortes, J.[2021]

In a phase I study of the selective JAK2 inhibitor XL019 involving 30 patients with myelofibrosis, all participants experienced neurotoxicity, leading to the study's termination after dose adjustments.

Despite the neurotoxicity, which resolved in half of the patients after stopping treatment, myelosuppression was minimal, and only 10% of patients showed defined responses according to International Working Group criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor. Verstovsek, S., Tam, CS., Wadleigh, M., et al.[2021]

Ruxolitinib, a JAK1/JAK2 inhibitor, has been shown to significantly reduce splenomegaly and improve symptoms and quality of life in patients with myelofibrosis, outperforming conventional chemotherapy.

Clinical trials indicate that ruxolitinib not only improves survival rates compared to placebo and best available therapies but also reduces JAK2 allele burden and stabilizes fibrosis in about 50% of patients, highlighting its effectiveness in modifying disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How ruxolitinib modified the outcome in myelofibrosis: focus on overall survival, allele burden reduction and fibrosis changes. Massaro, F., Molica, M., Breccia, M.[2021]

The study found that bone marrow fibroblasts in myelofibrosis patients are not part of the malignant cell clone, which challenges previous assumptions about their origin.

Two FDA-approved immunosuppressive drugs, cyclosporine and mycophenolate mofetil, were identified as effective in reducing fibroblast collagen production, suggesting they could be potential treatments to inhibit bone marrow fibrosis in myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fibroblast dynamics as an in vitro screening platform for anti-fibrotic drugs in primary myelofibrosis. Tomuleasa, C., Selicean, S., Gafencu, G., et al.[2022]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Novel treatments for myelofibrosis: beyond JAK inhibitors. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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]

3. Italy pubmed.ncbi.nlm.nih.gov

Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms. [2022]

4. England pubmed.ncbi.nlm.nih.gov

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]

5. United States pubmed.ncbi.nlm.nih.gov

Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor. [2021]

10. England pubmed.ncbi.nlm.nih.gov

How ruxolitinib modified the outcome in myelofibrosis: focus on overall survival, allele burden reduction and fibrosis changes. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Fibroblast dynamics as an in vitro screening platform for anti-fibrotic drugs in primary myelofibrosis. [2022]