Phase 2 Study of Selinexor for Myelofibrosis Progresses

A phase 2 study of selinexor (Xopvio) for the treatment of myelofibrosis (MF) has been initiated and the first patient has been dosed with the agent, according to a press release by Karyopharm Therapeutics Inc.¹

XPORT-MF-035 (NCT04562870) is a randomized, multi-center, open-label phase 2 study investigating the efficacy and safety of selinexor monotherapy in patients with MF.

“Myelofibrosis is a serious and life–threatening blood cancer defined by stem cell–derived clonal myeloproliferation, bone marrow fibrosis, anemia, enlarged spleen, low blood counts and short survival. With JAK inhibitors being the only class of drugs approved for this disease, there remains limited therapeutic options for patients who either progress following treatment with a JAK inhibitor or are intolerant. We believe selinexor has the potential to hold an important place in the myelofibrosis treatment paradigm and with dosing of the first patient underway, we plan to provide updates as the study progresses,” said Sharon Shacham, PhD, MBA, co-founder and chief scientific officer of Karyopharm, in a press release.

XPORT-MF-035 comes on the heels of positive preliminary data from the phase 2 ESSENTIAL trial (NCT03627403) of selinexor for the treatment of patients with MF who were previously treated with a JAK inhibitor. In the study, spleen volume reduction (SVR) of 35% or higher was achieved in 33% of patients that received at least 24 weeks of selinexor treatment. Response to selinexor were also durable. 

In XPORT-MF-035, approximately 112 patients with MF will be enrolled and randomized to either selinexor arm or the comparator arm. In the experimental arm, patients will be administered a 60 mg-dose of selinexor oral tablets once weekly on days 1, 8, 15, and 22 of each 28-day cycle. Those in the comparator will receive that physician’s choice of either ruxolitinib (Jakafi) retreatment, fedratinib (Inrebic), chemotherapy, anagrelide, corticosteroid, hematopoietic growth factor, immunomodulatory agent, androgen, or interferon. Treatment in the comparator arm may also include supportive care only with no MF treatment.²

The primary end point of the study is the percentage of patients with SVR ≥ 35% assessed by independent review committee (IRC). The key secondary end points include the percentage of patients with a SVR ≥ 50 by local assessment, the percentage with a SVR ≥ 25% by IRC assessment, overall survival, the percentage of patients with anemia response assessed by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).

Other secondary end points being explored include the following;

• duration of spleen volume reduction of ≥ 35% assessed by IRC
• duration of spleen volume reduction of ≥ 25% assessed by IRC
• duration of total symptom score is ≥ 50% by local assessment
• overall response rate assessed by IWG-MRT
• the number of participants with treatment-related adverse events
• pharmacokinetics.

At study sites in California, Colorado, and Georgia, patients with MF are actively being recruited to enroll in XPORT-MF-035. To be eligible, patients must be at least 18 years old with a diagnosis of primary MF or post-essential thrombocythemia, or post-polycythemia MF according to the 2016 World Health Organization classification of myeloproliferative neoplasms. Each patient's disease must be confirmed by the most recent local pathology report. All patients are required to be previously treated with JAK inhibition for at least 6 months and be relapsed, refractory, or intolerant to JAK inhibitors.

At screening, patients must have measurable splenomegaly as demonstrated by spleen volume of ≥ 450 cm3 by MRI or CT scan. Further, patients must have an ECOG performance score ≤ 2, and adequate laboratory tests. 

Patients with an MPN who have accelerated phase disease are ineligible for the study. Prior treatment with selinexor or other XPO1 inhibitors excludes patients from enrolling, as does use of any standard or experimental anti-MF therapy less than 21 days prior to cycle 1 day 1 in the study, strong cytochrome P450 3A inhibitors ≤ 7 days prior to selinexor dosing or strong CYP3A inducers ≤ 14 days prior to selinexor dosing, and having major surgery < 28 days prior to cycle 1 day 1.

In terms of comorbidities, patients are excluded from XPORT-MF-035 if they have uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days of first dosing in the study, impairment of gastrointestinal function or GI disease that may alter absorption of selinexor, or a life-threatening illness or condition that may interfere with study treatment. 

_References:

_{1. Karyopharm announces dosing of first patient in a new phase 2 study evaluating single-agent selinexor versus physician's choice in previously treated myelofibrosis. News release. Karyopharm Therapeutics, Inc. December 6, 2021. Accessed December 10, 2021. https://bit.ly/3dCKs1h}

_{2. A Study to evaluate safety and efficacy of selinexor versus treatment of physician's choice in participants with previously treated myelofibrosis. Clinicaltrials.gov. Accessed December 10, 2021. https://bit.ly/3DL8zp8}