On December 6, 2021 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported dosing of the first patient in a new Phase 2 study evaluating oral selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, as a monotherapy versus physician’s choice in patients with myelofibrosis (MF) previously treated with a JAK 1/2 inhibitor (XPORT-MF-035; NCT04562870) (Press release, Karyopharm, DEC 6, 2021, View Source [SID1234596468]).
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This randomized, multi-center, open-label Phase 2 study is designed to evaluate the safety and efficacy of selinexor monotherapy and is expected to enroll up to 112 patients, who will be randomized 1:1 to receive either low dose, once-weekly oral selinexor or physician’s standard treatment choice (per clinical practice). The primary endpoint of the study is the percentage of patients with spleen volume reduction (SVR) of ≥35% from baseline as assessed by an Independent Review Committee. The first patient has been dosed at the Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Meldola, Italy, by the Lead Principal Investigator, Dr. Alessandro Lucchesi, Sr. Consultant and Research Hematologist under the guide of Professor Giovanni Martinelli, the Chief Scientific Director.
Initiation of this Phase 2 study follows encouraging preliminary data from the Phase 2 ESSENTIAL trial, which will be highlighted in an oral presentation given by Srinivas Tantravahi, MBBS, MRCP, University of Utah Hospital, at the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual and Exposition on Saturday, December 11, 2021 at 1:00 p.m. ET. In the investigator-sponsored ESSENTIAL study (NCT03627403), which is evaluating selinexor in patients with MF previously treated with a JAK inhibitor, preliminary data showed that 33% of patients that received at least 24 weeks of selinexor treatment achieved ≥35% SVR. The responses were durable, and the first patient remained on study for more than two years. Patients had a median duration of 22 months of prior JAK inhibitor therapy with 11 out of 12 patients having disease refractory to ruxolitinib.
"As part of our strategic imperatives and pipeline priorities, we remain focused on diseases with the highest unmet needs and greatest potential to make an impact in patient outcomes," said Sharon Shacham, PhD, MBA, Co-Founder and Chief Scientific Officer of Karyopharm. "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."
About XPOVIO (selinexor)
XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. NEXPOVIO (selinexor) has also been granted conditional marketing authorization for adult patients with heavily pretreated multiple myeloma by the European Commission. Karyopharm’s supplemental New Drug Application (sNDA) requesting an expansion of its indication to include the treatment for patients with multiple myeloma after at least one prior therapy was approved by the FDA on December 18, 2020. In June 2020, Karyopharm received accelerated FDA approval of XPOVIO for its second indication in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including as a potential backbone therapy in combination with approved myeloma therapies (STOMP) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.
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XPOVIO (selinexor) is a prescription medicine approved:
In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (XVd).
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti–CD38 monoclonal antibody (Xd).
For the treatment of adult patients with relapsed or refractory diffuse large B–cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
SELECT IMPORTANT SAFETY INFORMATION
Warnings and Precautions
Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care.
Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony–stimulating factors.
Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care.
Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care.
Serious Infection: Monitor for infection and treat promptly.
Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes.
Embryo–Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception.
Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract.
Adverse Reactions
The most common adverse reactions (≥20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. Grade 3–4 laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON trial, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients. Treatment discontinuation rate due to adverse reactions was 19%.
The most common adverse reactions (≥20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.
The most common adverse reactions (incidence ≥20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3–4 laboratory abnormalities (≥15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL trial, fatal adverse reactions occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reactions was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients.