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1734 A Phase 1, Open-Label, Dose-Escalation Study of Selinexor Plus Ruxolitinib in Patients with Treatment-Naïve Myelofibrosis

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research, Combination therapy, Diseases, Therapies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Haris Ali, MD1, Ashwin Kishtagari, MBBS2, Keri Maher, DO3, Sanjay R Mohan, MD, MSCI4, Karen Ansaldo5*, Xulong Wang5*, Kamal Chamoun, MD5*, Josef T. Prchal, MD6 and Srinivas K. Tantravahi, MBBS7

1City of Hope Medical Center, Duarte, CA
2Division of Hematology & Oncology, Vanderbilt Ingram Cancer Center, Franklin, TN
3Massey Cancer Center, Virginia Commonwealth University, Tucson, AZ
4Vanderbilt University School of Medicine, Vanderbilt Ingram Cancer Center, Nashville, TN
5Karyopharm Therapeutics, Newton, MA
6Division of Hematology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
7Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

Background: Myelofibrosis (MF) is commonly associated with acquired somatic gene mutations in JAK2, CALR, or MPL. Spleen volume reduction and improvement in symptom burden of MF are attained in 40% of patients treated with the common front-line therapy ruxolitinib (RUX), a JAK1/2 inhibitor. Selinexor (SEL) is an oral Selective Inhibitor of Nuclear Export (SINE) compound that inhibits exportin-1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins (e.g., TP53, IkB, p21), reduction in oncoprotein mRNAs (c-Myc, Bcl-2, Bcl-6, cyclin D) and selective apoptosis of cancer cells. Selinexor has received FDA approval for use in patients with multiple myeloma and diffuse large B-cell lymphoma. Preclinical studies demonstrated activity with the combination of SEL plus RUX. In patients with disease refractory to a JAK inhibitor (JAKi), SEL monotherapy had notable clinical activity and a generally manageable safety profile (NCT03627403).

Methods: The ongoing multicenter, open-label, Phase 1/2 study (NCT04562389) is evaluating the safety and efficacy of SEL plus RUX in treatment-naïve MF patients. Two dose levels of SEL were evaluated, 40mg and 60mg orally once-weekly (QW) plus RUX twice daily (BID) as per label in 28-day cycles. For nausea prophylaxis, all patients received a 5-HT3 antagonist prior to each dose SEL and then as needed. Primary objectives include safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and preliminary efficacy. Secondary objectives include spleen, symptom, and anemia response, and overall survival.

Results: As of July 2022, 19 patients have received at least one dose of oral 40mg (n=4) or 60mg (n=15) weekly SEL with RUX twice daily as per standard of care. Median age was 64 years old (range 44-77). Nine patients had primary MF, 7 had post-ET MF, and 3 had post-PV MF. At baseline, two patients had packed red blood cell (PRBC) transfusion-dependent anemia. DIPSS risk category was int-1 (n=6), int-2 (n=9), and high risk (n=4). Of patients evaluable for spleen response, 11/14 achieved spleen volume reduction of ≥35% (SVR35) at week 12 (79%, 95% CI: 49% to 95%) and 6/7 achieved SVR35 at week 24 (86%, 95% CI: 42% to 100%). Eighty-six percent (12/14) (95% CI: 57% to 98%) of patients achieved SVR35 at any time on study. Thirteen patients with available data and who received at least 12 weeks of treatment were evaluated for symptom response; 9/13 (69%, 95% CI: 39% to 91%) had a total symptom score ≥50% reduction by week 12. Eleven out of 17 PRBC transfusion-independent patients (65%) who received at least 8 weeks of therapy maintained stable hemoglobin (Hgb; ± 2g/dL) or improved Hgb levels (>2g/dL increase) at the last follow up. The most common treatment-emergent adverse events (TEAEs) were nausea (11/19, 58%), anemia (8/19, 42%) and vomiting (8/19, 42%). The most common Grade 3 TEAEs were thrombocytopenia and anemia, with only two Grade 4 TEAEs (thrombocytopenia).

Conclusions: In this preliminary analysis, the combination of SEL and RUX shows promising clinical activity to date in patients with treatment-naïve myelofibrosis. The combination has been reasonably well-tolerated and with a manageable side effect profile to date.

Disclosures: Ali: Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Kishtagari: CTI Biopharm: Speakers Bureau. Maher: BMS: Research Funding. Mohan: Incyte: Research Funding; Astex: Research Funding. Ansaldo: Karyopharm: Current Employment. Wang: Karyopharm: Current Employment. Chamoun: Karyopharm: Current Employment. Tantravahi: Karyopharm Therapeutics Inc., Novartis, AbbVie, Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.,: Research Funding.

*signifies non-member of ASH