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236 Efficacy and Safety of Add-on Parsaclisib to Ruxolitinib Therapy in Myelofibrosis Patients With Suboptimal Response to Ruxolitinib: Final Results From a Phase 2 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Latest Data for Combination and Emerging Targeted Therapies in Myelofibrosis
Hematology Disease Topics & Pathways:
Research, clinical trials, MPN, Clinical Research, Combination therapy, Chronic Myeloid Malignancies, Diseases, Therapies, Myeloid Malignancies
Saturday, December 10, 2022: 2:15 PM

Abdulraheem Yacoub, MD1, Uma Borate, MD2, Raajit K Rampal, MD, PhD3, Haris Ali, MD4, Eunice Wang, MD5*, Aaron T. Gerds, MD, MS6, Gabriela S. Hobbs, MD7, Marina Kremyanskaya, MD, PhD8, Elliott Winton, MD9, Casey O’Connell, MD10*, Swati Goel, MD11*, Stephen T Oh, MD, PhD12, Gary J. Schiller, MD13, Albert Assad, MD14*, Sue Erickson-Viitanen, PhD14*, Feng Zhou, PhD14* and Naval Daver, MD15

1University of Kansas Cancer Center, Westwood, KS
2Oregon Health & Science University, Portland, OR
3Memorial Sloan Kettering Cancer Center, New York, NY
4City of Hope Medical Center, Duarte, CA
5Roswell Park Cancer Institute, BUFFALO, NY
6Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
7Massachusetts General Hospital, Boston, MA
8Icahn School of Medicine at Mount Sinai, New York, NY
9Emory University, Atlanta, GA
10University of Southern California, Los Angeles, CA
11Montefiore Medical Center, Bronx, NY
12Washington University School of Medicine, St. Louis, MO
13David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
14Incyte Corporation, Wilmington, DE
15University of Texas MD Anderson Cancer Center, Houston, TX

Background: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor and is effective in patients (pts) with myelofibrosis (MF). However, suboptimal or declining responses to RUX occur in a subset of pts, possibly due to persistent PI3K pathway activation with chronic JAK inhibitor therapy. Parsaclisib is a potent and highly selective next-generation PI3Kδ inhibitor. We conducted a phase 2 study (NCT02718300) evaluating add-on parsaclisib to stable doses of RUX, for pts with MF who experienced a suboptimal response to RUX (Yacoub A. HemaSphere 2021;5 Suppl 2:512). Here we report efficacy and safety results from the completed study.

Methods: Eligible pts had primary or post-essential thrombocythemia/post-polycythemia vera MF with suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM], or palpable splenomegaly 5-10 cm below LSM and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 each using the Screening Symptom Form) after ≥6 months of RUX (5-25 mg twice daily; RUX stable dose, ≥8 wks). Pts remained on their stable RUX dose and were randomized to receive add-on parsaclisib 10 mg or 20 mg once daily (QD) for 8 wks and the same dose once weekly (QW) thereafter (QD/QW group), or parsaclisib 5 mg or 20 mg QD for 8 wks and 5 mg QD thereafter (all QD group) (Figure). Primary efficacy endpoint was change in spleen volume (SV) from baseline to wk 12 by MRI/CT scan. Key secondary endpoints included change in SV to wk 24, change in total symptom score (MFSAF-TSS, MPN-SAF-TSS), and safety.

Results: Overall, 32 pts received parsaclisib QD/QW and 42 pts received parsaclisib all QD. Baseline median age was 68.0 (range 41.0-89.0) years and 47.3% of pts were male. The study has been completed. Median treatment duration was 336.5 days; median average daily dose was 5.0 mg/day for parsaclisib and 29.8 mg/day for RUX. Among all pts, 16 (21.6%) were rolled over to continue therapy in an open-label parsaclisib study after ending treatment in the present study. Other common reasons for pts discontinuing treatment were adverse events (13 [17.6%]) and progressive disease (10 [13.5%]); remainder discontinued for physician decision, pt decision, or “Other.” Baseline median SV (cm3) was 2414.5 in QD/QW (n=29) and 1877.5 in QD (n=37); median MFSAF-TSS was 10.8 (n=28) and 16.3 (n=32) and median MPN-SAF-TSS was 25.5 (n=28) and 30.0 (n=37), respectively.

Median percentage change in SV at wk 12 was −1.6 (n=28) in QD/QW and −15.4 (n=37) in QD, and at wk 24 was −2.5 (n=20) and −19.3 (n=29), respectively. Median percentage change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW and −32.8 (n=24) in QD, and at wk 24 was −10.0 (n=16) and −44.4 (n=18), respectively. Median percentage change in MPN-SAF-TSS at wk 12 was −19.2 (n=20) in QD/QW and −39.8 (n=30) in QD, and at wk 24 was −43.3 (n=15) and −60.8 (n=26), respectively. Responder analysis for these 3 efficacy variables is shown in the Table.

Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. Grade 3/4 nonhematologic TEAEs occurring in >1 pt overall were pneumonia (n=5; 3 QD/QW, 2 QD), fatigue, hypoxia (each n=2; each 1 QD/QW, 1 QD), dyspnea (n=2, all QD), fall, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hypocalcemia (each n=2; all QD/QW). New-onset grade 3 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 11/42 pts (26.2%) in QD; grade 4 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 3/42 pts (7.1%) in QD. TEAEs of special interest included grade ≥3 ALT and AST (each n=2; all QD/QW), grade ≥2 diarrhea (n=4) and rash (n=1) (all QD/QW), and any-grade herpes simplex (n= 4; 1 QD/QW, 3 QD) and VZV infection (n= 3; 1 QD/QW, 2, QD). No colitis was reported. TEAEs led to parsaclisib interruption in 16/32 pts in QD/QW and 22/42 pts in QD, and RUX interruption in 5/32 and 8/42 pts, respectively. TEAEs led to parsaclisib discontinuation in 5/32 pts in QD/QW and 4/42 pts in QD, and RUX discontinuation in 2/32 and 2/42 pts, respectively.

Conclusion: Final results from the phase 2 study demonstrate improvement in symptoms and SV with add-on parsaclisib in patients with MF having a suboptimal response to ruxolitinib. All daily dosing regimens were more efficacious than daily/weekly dosing. Combination therapy was associated with limited grade 3/4 AEs and TEAE-related discontinuations. Phase 3 studies using 5 mg QD parsaclisib together with ruxolitinib in naive MF patients and ruxolitinib-experienced patients are in progress.

Disclosures: Yacoub: AbbVie: Consultancy; Agios: Consultancy; Servier: Consultancy; Stemline Therapeutics: Research Funding; Notable Labs: Consultancy; Gilead: Consultancy; Apellis: Consultancy; Acceleron Pharma: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; PharmaEssentia: Consultancy; CTI Pharma: Consultancy; Incyte: Consultancy, Speakers Bureau. Borate: Jazz: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ali: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees. Wang: AbbVie, Astellas, Daiichi Sankyo, Dava Oncology (Arog), Gilead, Genentech, Jazz Pharmaceuticals, Kite Pharmaceuticals, Kura Oncology, MacroGenics, Pfizer, PTC Therapeutics, Stemline Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Genentech, Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Independent data review committees; Pfizer, Stemline Therapeutics: Other: Speaker. Gerds: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Accurate Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imago BioSciences: Research Funding; Kratos Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys/Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hobbs: Bayer: Research Funding; Pharmaxis: Other: Advisor or review panel participant; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; Constellation: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; PI, Research Funding; Pfizer: Other: Advisor or review panel participant; Incyte: Other: Advisor or review panel participant; PI, Research Funding; Bristol Myers Squibb Co./Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; Keros: Other: Advisor or review panel participant; Merck: Research Funding. Kremyanskaya: Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; Ionis: Research Funding; Incyte: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Chimerix: Research Funding; Kronos: Research Funding; Kura: Research Funding; BMS: Research Funding. Winton: Blueprint Medicines Corporation, Samus Therapeutics and Incyte Corporation: Research Funding. O’Connell: Astex Pharmaceuticals, Genentech: Research Funding; Astex Pharmaceuticals, Bristol Myers Squibb, Pfizer, Shionogi: Membership on an entity's Board of Directors or advisory committees. Oh: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgne/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cogent: Consultancy. Schiller: Medimmune: Research Funding; Sangamo: Research Funding; Regimmune: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding, Speakers Bureau; Sellas: Research Funding; Pfizer: Research Funding; PreCOG LLC: Research Funding; Deciphera: Research Funding; Astellas: Research Funding, Speakers Bureau; Samus: Research Funding; Amgen: Current equity holder in publicly-traded company, Honoraria; Johnson & Johnson: Current equity holder in publicly-traded company; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Deltafly: Research Funding; Cellectis: Research Funding; AVM Biopharma: Research Funding; Glycomimetics: Research Funding; Trovagen: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Jazz: Consultancy; Gamida: Research Funding; Ono Pharma: Honoraria; FujiFilm: Research Funding; Genentech-Roche: Research Funding; Tolero: Research Funding; Cyclacel: Research Funding; AltruBio: Research Funding; Kite, a Gilead Company: Research Funding, Speakers Bureau; Stemline: Research Funding; AstraZeneca: Honoraria; Takeda: Research Funding; Mateon: Research Funding; Geron: Research Funding; Onconova: Research Funding; Actuate: Research Funding; Arog: Research Funding; Forma: Research Funding; Janssen: Research Funding; Stemline: Speakers Bureau; Novartis: Honoraria, Other: Speaker fees, Research Funding; Millennium: Research Funding; Cellerant: Research Funding; CTI: Research Funding; Constellation: Research Funding; Daiichi-Sankyo: Research Funding; Agios: Consultancy, Honoraria; Actinium: Research Funding; AbbVie: Research Funding, Speakers Bureau. Assad: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Erickson-Viitanen: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zhou: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Daver: Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding.

OffLabel Disclosure: Parsaclisib is an investigational drug being assessed in combination with ruxolitinib for patients with myelofibrosis

*signifies non-member of ASH