Selinexor + Ruxolitinib for Myelofibrosis

(SENTRY Trial)

Recruiting at 150 trial locations

Overseen By Mohit Narang

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Karyopharm Therapeutics Inc

Must be taking: JAK inhibitors

Must not be taking: JAK inhibitors, XPO1 inhibitors

Disqualifiers: Accelerated phase, Blast phase, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This is a global, multicenter, 2-part study to evaluate the efficacy and safety of selinexor plus ruxolitinib in JAK inhibitor (JAKi) treatment-naïve myelofibrosis (MF) participants. The study will be conducted in two phases: Phase 1 (open-label) and Phase 3 (double-blind). Phase 1 (enrollment completed) was an open-label evaluation of the safety and recommended Phase 2 dose (RP2D) of selinexor in combination with ruxolitinib and included a dose escalation using a standard 3+3 design (Phase 1a) and a dose expansion part (Phase 1b). Phase 3 (ongoing), double-blind, placebo-controlled part of the study comparing the efficacy and safety of combination therapy of selinexor + ruxolitinib with combination of placebo + ruxolitinib.

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 combination Selinexor and Ruxolitinib for treating myelofibrosis?

Research shows that Ruxolitinib, one of the drugs in the combination, is effective in reducing spleen size and improving symptoms in myelofibrosis patients, with benefits in quality of life and survival. It has been shown to work well even in patients with low platelet counts, although it can cause anemia and low platelet levels, which are manageable. ^{1 2 3 4 5}

Is the combination of Selinexor and Ruxolitinib safe for treating myelofibrosis?

Ruxolitinib, used for myelofibrosis, is generally safe but can cause low blood cell counts, like anemia (low red blood cells) and thrombocytopenia (low platelets), which are manageable and rarely lead to stopping treatment. No new safety concerns were found in large studies, but specific safety data for the combination with Selinexor is not provided. ^{1 2 3 5 6}

How does the drug combination of Selinexor and Ruxolitinib differ from other treatments for myelofibrosis?

The combination of Selinexor and Ruxolitinib for myelofibrosis is unique because it combines Ruxolitinib, a JAK1/JAK2 inhibitor that reduces spleen size and symptoms, with Selinexor, which may offer additional benefits through its novel mechanism of inhibiting nuclear export. This combination aims to enhance treatment effectiveness and potentially overcome resistance or suboptimal responses seen with Ruxolitinib alone. ^{1 2 4 5 7}

Eligibility Criteria

Adults diagnosed with primary or secondary myelofibrosis, showing significant spleen enlargement and certain risk levels. They must have functioning major organs, no prior treatments with JAK inhibitors or selinexor, not be pregnant or breastfeeding, agree to use contraception, and have a life expectancy over 6 months. Exclusions include recent surgeries, uncontrolled infections without stable treatment for hepatitis B/C or HIV.

Inclusion Criteria

I have hepatitis B but have been on antiviral therapy for over 8 weeks and my viral load is under 100 IU/mL.

I will use effective birth control and not donate sperm during and for 90 days after treatment.

I have been diagnosed with a specific type of bone marrow disorder according to the latest standards.

Exclusion Criteria

I have a history of high blood pressure in the lungs.

Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participants safety, prevent the participant from giving informed consent, or being compliant with the study procedures, or confound the ability to interpret study results.

I cannot tolerate two different anti-nausea medications for at least 2 treatment cycles.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Open-label evaluation of the safety and recommended Phase 2 dose (RP2D) of selinexor in combination with ruxolitinib, including dose escalation and expansion

Varies per cohort

Weekly visits for dosing

Phase 3 Treatment

Double-blind, placebo-controlled part of the study comparing the efficacy and safety of selinexor + ruxolitinib with placebo + ruxolitinib

28-day cycles

Weekly visits for dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ruxolitinib (Janus Kinase (JAK) Inhibitor)
• Selinexor (Selective Inhibitor of Nuclear Export (SINE))

Trial Overview The trial is testing the combination of Selinexor and Ruxolitinib against a placebo plus Ruxolitinib in patients who haven't used JAK inhibitors before. It's split into two phases: an initial phase to determine safe dosages followed by a larger phase where participants are randomly assigned to either the drug combo or placebo in a 2:1 ratio.

Participant Groups

Group I: Phase 3: Selinexor 60 mg + Ruxolitinib BID Experimental Treatment 2 Interventions

Participants with MF will receive a fixed starting dose of 60 mg selinexor (RD) oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with a starting dose of 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count.

Group II: Phase 1b: Selinexor and Ruxolitinib BID Experimental Treatment 2 Interventions

Participants with MF will receive a dose of 40 or 60 mg selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count.

Group III: Phase 1a: Cohort 2: Selinexor 60 mg + Ruxolitinib BID Experimental Treatment 2 Interventions

Participants with MF will receive a dose of 60 mg selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count.

Group IV: Phase 1a: Cohort 1: Selinexor 40 mg + Ruxolitinib BID Experimental Treatment 2 Interventions

Participants with MF will receive a dose of 40 milligrams (mg) selinexor oral tablets once weekly (QW) on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib twice a day (BID) based on the participants baseline platelet count.

Group V: Phase 3: Placebo + Ruxolitinib BID Active Control 2 Interventions

Participants with MF will receive a matching placebo of selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with a starting dose of 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count.

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

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 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]

Ruxolitinib is a selective oral inhibitor of JAK1 and JAK2 that effectively reduces spleen size and alleviates symptoms in patients with myelofibrosis, showing a 41.9% spleen-volume response rate compared to only 0.7% for placebo in a Phase III trial.

Patients taking ruxolitinib also experienced significant improvements in their overall quality of life and symptom scores, with 45.9% showing a ≥ 50% improvement compared to 5.3% for placebo, although the treatment was associated with thrombocytopenia as a dose-limiting toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Ostojic, A., Vrhovac, R., Verstovsek, S.[2021]

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]

Ruxolitinib, a JAK1/JAK2 inhibitor, was evaluated in a large phase 3b study (N = 2233) for treating myelofibrosis, including patients with low platelet counts, showing significant reductions in spleen size and symptoms.

The safety profile of ruxolitinib was consistent with previous studies, with common adverse events like anemia and thrombocytopenia, but these rarely led to treatment discontinuation, indicating it is a viable option for patients with low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Al-Ali, HK., Griesshammer, M., Foltz, L., et al.[2021]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

Ruxolitinib is a dual inhibitor of JAK1 and JAK2, which are crucial in the development of myelofibrosis (MF), and it has been FDA-approved since November 2011 for treating intermediate or high-risk MF.

The review discusses Ruxolitinib's current role in managing MF and explores its potential future applications in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janus activated kinase inhibition in myelofibrosis. Malhotra, H.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. [2021]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. [2021]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. [2021]

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

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]

7. India pubmed.ncbi.nlm.nih.gov

Janus activated kinase inhibition in myelofibrosis. [2021]