NEWTON, Mass. – Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced that health-related quality of life (HRQoL) data from the Phase 3 portion of the SEAL (Selinexor in Advanced Liposarcoma) study were published online in Future Oncology. The SEAL study evaluated twice weekly, single agent selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, versus matching placebo in patients with advanced unresectable dedifferentiated liposarcoma (DDLPS) who have experienced disease progression following at least two prior therapies. XPOVIO® (selinexor) is currently approved by the U.S. Food & Drug Administration (FDA) for the treatment of relapsed or refractory multiple myeloma and relapsed or refractory diffuse large B-cell lymphoma; XPOVIO has not been approved for the treatment of DDLPS and, therefore, its safety and efficacy for that patient population have not been established.
“The Phase 3 SEAL study suggests that selinexor has enhanced clinical activity and a manageable safety profile in patients with DDLPS, a very rare and aggressive form of cancer where there are very few treatment options available. In addition to meeting its primary endpoint with a statistically significant improvement in progression-free survival (PFS), treatment with selinexor also resulted in improvements in key quality of life parameters as compared to patients treated with placebo,” said Jatin Shah, MD, Chief Medical Officer of Karyopharm. “The results highlight that the reduction in tumor growth, as measured by objective radiographic PFS, is accompanied by clinically important reductions in pain, with minimal effects on other aspects of quality of life. Since pain is one of the most devastating symptoms associated with advanced and progressing DDLPS, the significant reduction in pain, and a delay in the time to definitive deterioration reported by patients in the selinexor arm, combined with the convenience of an orally administered therapy, could represent a meaningful clinical benefit to patients.”
“We are pleased to see the first set of data from the Phase 3 SEAL study now published in a peer-reviewed medical journal,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. “These data continue to support our overarching development strategy to pursue additional solid tumor indications where we believe selinexor can demonstrate meaningful clinical activity both as a single agent, and more importantly, as part of future combination regimens for patients battling cancer.”
The Phase 3 SEAL Study Health-Related Quality of Life Results
The published SEAL study results were based on the randomized, double blind, placebo-controlled, cross-over, Phase 3 portion of the study, which evaluated oral selinexor versus matching placebo in 285 adult patients with advanced unresectable DDLPS. The secondary endpoint of the SEAL study measured HRQoL outcomes by using the EORTC QLQ-C30 questionnaire, which was completed by 255 patients in the study. Overall, the results showed that pain scores worsened in the placebo arm compared to the selinexor arm across all post-baseline visits, though some visits were not statistically significant. The patients who received twice-weekly selinexor also reported lower rates and slower worsening of pain over time and a longer time to marked clinical deterioration of pain compared to patients treated with placebo. Median time to next treatment was also significantly longer in patients receiving selinexor compared to those receiving placebo. These results indicate that reduction in tumor growth (as measured by objective radiographic PFS) is accompanied by clinically important reduction in pain, with minimal effects on other aspects of quality of life.
About the SEAL Study
SEAL (Selinexor in Advanced Liposarcoma) was a Phase 2/3, randomized, double blind, placebo-controlled, multicenter study (NCT02606461) designed to evaluate the efficacy and safety of twice-weekly, 60mg fixed dose of selinexor in patients with advanced unresectable dedifferentiated liposarcoma following at least two prior therapies. The Phase 3 portion of the study enrolled 285 patients (2:1 randomization). Patients on the placebo arm with confirmed progressive disease were permitted to cross over to the selinexor treatment arm. The primary endpoint of the study was PFS and secondary endpoint measured HRQoL outcomes. In the study, selinexor was associated with a 30% reduction in the time to disease progression or death in the Phase 3 portion (hazard ratio (HR)=0.70; p=0.023, medians 2.83 months on selinexor compared to 2.07 months on placebo).
The most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms and were consistent with those previously reported from other selinexor studies. Most AEs were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (81%), decreased appetite (60%), fatigue (51%), and vomiting (49%) and were mostly Grade 1 and 2 events. The most common Grade 3 and 4 treatment-related AEs were anemia (19%), hyponatremia (11%), thrombocytopenia (10%) and asthenia (10%).
About Liposarcoma
Liposarcoma is a rare type of cancer that occurs in the fat cells in the body, most often in the muscles of the limbs or abdomen. Dedifferentiated liposarcoma is a high grade type of liposarcoma that grows more aggressively than a low grade, well differentiated liposarcoma and is associated with poorer prognosis.¹ Liposarcoma accounts for approximately 20% of all soft tissue sarcomas.² In liposarcoma, the risk of recurrence and metastasis increases with higher grade disease.³
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. The safety and efficacy of selinexor for use in in patients with DDLPS has not been established; selinexor has not been approved for this use by the U.S. Food and Drug Administration (FDA) or any other regulatory agency. Karyopharm received accelerated approval of XPOVIO in July 2019 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. NEXPOVIO® (selinexor) has also been granted conditional marketing authorization in combination with dexamethasone for adult patients with heavily pretreated multiple myeloma by the European Commission. Karyopharm’s supplemental New Drug Application 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 2 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), 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.
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.
Use In Specific Populations
Lactation: Advise not to breastfeed.
For additional product information, including full prescribing information, please visit www.XPOVIO.com.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1–888–209–9326 or FDA at 1–800–FDA–1088 or www.fda.gov/medwatch.
About Karyopharm Therapeutics
Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company pioneering novel cancer therapies and dedicated to the discovery, development, and commercialization of first-in-class drugs directed against nuclear export for the treatment of cancer and other diseases. Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). Karyopharm’s lead compound, XPOVIO® (selinexor), is approved in the U.S. in multiple hematologic malignancy indications, including in combination with Velcade® (bortezomib) and dexamethasone for the treatment of adult patients with multiple myeloma after at least one prior therapy, in combination with dexamethasone for the treatment of adult patients with heavily pretreated multiple myeloma and as a monotherapy for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma. NEXPOVIO® (selinexor) has also been granted conditional marketing authorization for adult patients with heavily pretreated multiple myeloma by the European Commission. In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm has several investigational programs in clinical or preclinical development. For more information, please visit www.karyopharm.com.
XPOVIO® and NEXPOVIO® are registered trademarks of Karyopharm Therapeutics Inc. Velcade® is a registered trademark of Takeda Pharmaceutical Company Limited.
References
1 Livingston, J.A., et al. Role of chemotherapy in dedifferentiated liposarcoma of the retroperitoneum: defining the benefit and challenges of the standard. Sci Rep 7, 11836 (2017).
https://doi.org/10.1038/s41598-017-12132-w
2 https://pubmed.ncbi.nlm.nih.gov/25115417/
3 http://sarcomahelp.org/liposarcoma.html
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