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ADD-ON PARSACLISIB (A PI3K-DELTA INHIBITOR) IN PATIENTS WITH MYELOFIBROSIS AND SUBOPTIMAL RESPONSE TO RUXOLITINIB: INTERIM ANALYSIS FROM A PHASE 2 STUDY
Author(s): ,
Abdulraheem Yacoub
Affiliations:
University of Kansas Cancer Center,Westwood,United States
,
Uma Borate
Affiliations:
Oregon Health & Science University,Portland,United States
,
Raajit Rampal
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Haris Ali
Affiliations:
City of Hope National Medical Center,Duarte,United States
,
Eunice Wang
Affiliations:
Roswell Park Cancer Institute,Buffalo,United States
,
Aaron Gerds
Affiliations:
Cleveland Clinic,Cleveland,United States
,
Gabriela Hobbs
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Marina Kremyanskaya
Affiliations:
Icahn School of Medicine at Mount Sinai,Manhattan,United States
,
Elliott Winton
Affiliations:
Emory University,Atlanta,United States
,
Casey O'Connell
Affiliations:
University of Southern California,Los Angeles,United States
,
Swati Goel
Affiliations:
Montefiore Medical Center,Bronx,United States
,
Stephen Oh
Affiliations:
Washington University School of Medicine,St Louis,United States
,
Gary Schiller
Affiliations:
University of California Los Angeles,Los Angeles,United States
,
Albert Assad
Affiliations:
Incyte Corporation,Wilmington,United States
,
Sue Erickson-Viitanen
Affiliations:
Incyte Corporation,Wilmington,United States
,
Xuejun Chen
Affiliations:
Incyte Corporation,Wilmington,United States
,
Feng Zhou
Affiliations:
Incyte Corporation,Wilmington,United States
Naval Daver
Affiliations:
University of Texas MD Anderson Cancer Center,Houston,United States
EHA Library. Yacoub A. 06/09/21; 324798; EP1075
Abdulraheem Yacoub
Abdulraheem Yacoub
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1075

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Ruxolitinib (rux) is highly effective in myelofibrosis (MF). Rux improves symptoms, reduces spleen size, and prolongs survival; however, suboptimal response may occur in a subset of patients (pts), potentially due to persistent PI3K/AKT pathway activation despite continued JAK inhibition. Parsaclisib (INCB050465) is a potent and highly selective next-generation PI3Kδ inhibitor. We hypothesized that adding parsaclisib would improve outcomes in pts with suboptimal response to stable rux treatment.

Aims
This phase 2 study (NCT02718300) evaluated optimal dosing, efficacy, and safety of add-on parsaclisib in pts with MF with a suboptimal response to rux.

Methods
Pts had primary, post–polycythemia vera, or post–essential thrombocythemia MF, ECOG performance status ≤2, and 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 weeks [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 1). The primary endpoint was change in spleen volume from baseline to wk 12 by MRI/CT scan; other endpoints included change in spleen length and symptoms (Myelofibrosis-Symptoms Assessment Form Total Symptom Score [MFSAF-TSS]).

Results
At data cutoff (Aug 27, 2020) for this interim analysis, 32 pts received parsaclisib QD/QW and 35 received parsaclisib all QD. Median treatment duration was 213 days; median average daily dose was 5.0 mg/day for parsaclisib and 30.0 mg/day for rux. Baseline median spleen volume (cm3) was 2414 in QD/QW (n=29) and 1885 in QD (n=29); median MFSAF-TSS was 10.8 (n=28) and 16.3 (n=26), respectively. Median percentage change in spleen volume at wk 12 was −1.9 (n=29) in QD/QW and −13.0 (n=27) in QD, and at wk 24 was −3.5 (n=23) and −21.8 (n=17), respectively (Figure 2: [A] spleen volume reduction; [B] palpable spleen length change). Median percentage change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW and −37.4 (n=17) in QD.

Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2; grade 3/4 nonhematologic TEAEs occurring in >1 pt overall were urinary tract infection (n=3; all QD/QW), fall, increased alanine aminotransferase, increased aspartate aminotransferase, hypocalcemia, and hypertension (each n=2; all QD/QW), dyspnea (n=2; both QD), and fatigue and pneumonia (each n=2; each 1 QD/QW, 1 QD). New-onset grade 3 thrombocytopenia was observed in 6/32 (19%) pts in QD/QW and 9/35 (26%) pts in QD; grade 4 thrombocytopenia was observed in 6/32 (19%) pts in QD/QW and 1/35 (3%) pts in QD. TEAEs of special interest included grade ≥2 diarrhea (n=4) and grade ≥2 rash (n=1) (all QD/QW). No colitis was reported. TEAEs led to parsaclisib interruption in 18/32 pts in QD/QW and 18/35 pts in QD, and rux interruption in 6/32 and 8/35 pts, respectively; and to parsaclisib discontinuation in 7/32 pts in QD/QW and 3/35 pts in QD, and rux discontinuation in 2/32 and 1/35 pts, respectively.

Conclusion
Add-on parsaclisib showed preliminary efficacy in pts with MF experiencing suboptimal response to rux; QD dosing appeared more efficacious than QD/QW dosing. Combination therapy was generally well tolerated with limited grade 3/4 AEs and TEAE-related discontinuations.

Keyword(s): Myelofibrosis, Phase II, PI3K, Ruxolitinib

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1075

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Ruxolitinib (rux) is highly effective in myelofibrosis (MF). Rux improves symptoms, reduces spleen size, and prolongs survival; however, suboptimal response may occur in a subset of patients (pts), potentially due to persistent PI3K/AKT pathway activation despite continued JAK inhibition. Parsaclisib (INCB050465) is a potent and highly selective next-generation PI3Kδ inhibitor. We hypothesized that adding parsaclisib would improve outcomes in pts with suboptimal response to stable rux treatment.

Aims
This phase 2 study (NCT02718300) evaluated optimal dosing, efficacy, and safety of add-on parsaclisib in pts with MF with a suboptimal response to rux.

Methods
Pts had primary, post–polycythemia vera, or post–essential thrombocythemia MF, ECOG performance status ≤2, and 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 weeks [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 1). The primary endpoint was change in spleen volume from baseline to wk 12 by MRI/CT scan; other endpoints included change in spleen length and symptoms (Myelofibrosis-Symptoms Assessment Form Total Symptom Score [MFSAF-TSS]).

Results
At data cutoff (Aug 27, 2020) for this interim analysis, 32 pts received parsaclisib QD/QW and 35 received parsaclisib all QD. Median treatment duration was 213 days; median average daily dose was 5.0 mg/day for parsaclisib and 30.0 mg/day for rux. Baseline median spleen volume (cm3) was 2414 in QD/QW (n=29) and 1885 in QD (n=29); median MFSAF-TSS was 10.8 (n=28) and 16.3 (n=26), respectively. Median percentage change in spleen volume at wk 12 was −1.9 (n=29) in QD/QW and −13.0 (n=27) in QD, and at wk 24 was −3.5 (n=23) and −21.8 (n=17), respectively (Figure 2: [A] spleen volume reduction; [B] palpable spleen length change). Median percentage change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW and −37.4 (n=17) in QD.

Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2; grade 3/4 nonhematologic TEAEs occurring in >1 pt overall were urinary tract infection (n=3; all QD/QW), fall, increased alanine aminotransferase, increased aspartate aminotransferase, hypocalcemia, and hypertension (each n=2; all QD/QW), dyspnea (n=2; both QD), and fatigue and pneumonia (each n=2; each 1 QD/QW, 1 QD). New-onset grade 3 thrombocytopenia was observed in 6/32 (19%) pts in QD/QW and 9/35 (26%) pts in QD; grade 4 thrombocytopenia was observed in 6/32 (19%) pts in QD/QW and 1/35 (3%) pts in QD. TEAEs of special interest included grade ≥2 diarrhea (n=4) and grade ≥2 rash (n=1) (all QD/QW). No colitis was reported. TEAEs led to parsaclisib interruption in 18/32 pts in QD/QW and 18/35 pts in QD, and rux interruption in 6/32 and 8/35 pts, respectively; and to parsaclisib discontinuation in 7/32 pts in QD/QW and 3/35 pts in QD, and rux discontinuation in 2/32 and 1/35 pts, respectively.

Conclusion
Add-on parsaclisib showed preliminary efficacy in pts with MF experiencing suboptimal response to rux; QD dosing appeared more efficacious than QD/QW dosing. Combination therapy was generally well tolerated with limited grade 3/4 AEs and TEAE-related discontinuations.

Keyword(s): Myelofibrosis, Phase II, PI3K, Ruxolitinib

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