TY - JOUR
T1 - Phase 1 study of the PI3Kd inhibitor INCB040093 6 JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma
AU - Phillips, Tycel J.
AU - Forero-Torres, Andres
AU - Sher, Taimur
AU - Diefenbach, Catherine S.
AU - Johnston, Patrick
AU - Talpaz, Moshe
AU - Pulini, Jennifer
AU - Zhou, Li
AU - Scherle, Peggy
AU - Chen, Xuejun
AU - Barr, Paul M.
N1 - Funding Information:
Conflict-of-interest disclosure: T.J.P. had a consulting/advisory role for Pharmacyclics and Seattle Genetics and received travel/accommodation expenses from Incyte; A.F.-T. participated in a speakers’ bureau for Seattle Genetics and received institutional research funding from Daiichi Sankyo, Genentech/Roche, Gilead Sciences, Immunomedics, Novartis, Oncothyreon, Pfizer, Seattle Genetics, Syndax, and TRACON Pharma. T.S. had a consulting role for Janssen. C.S.D. received research funding from Incyte and had a consulting role for Janssen and Seattle Genetics. P.J. has nothing to disclose. M.T. received research funding from Ariad, Incyte, Novartis, Pfizer, and Sanofi. J.P. is an employee of and has stock ownership with Incyte. L.Z. is an employee of and has stock ownership with Incyte. P.S. is an employee of and has stock ownership with Incyte. X.C. is an employee of and has stock ownership with Incyte. P.M.B. had a consulting role for Gilead and Verastem.
Publisher Copyright:
© 2018 by The American Society of Hematology
PY - 2018/7/19
Y1 - 2018/7/19
N2 - Because both phosphatidylinositol 3-kinase d (PI3Kd) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kd inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n 5 49; combination therapy, n 5 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily 1 itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n 5 5) and pyrexia (n 5 4), and with combination Pneumocystis jiroveci pneumonia (n 5 5), pneumonia (unrelated to P jiroveci; n 5 5), and pyrexia (n 5 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813. (Blood.
AB - Because both phosphatidylinositol 3-kinase d (PI3Kd) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kd inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n 5 49; combination therapy, n 5 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily 1 itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n 5 5) and pyrexia (n 5 4), and with combination Pneumocystis jiroveci pneumonia (n 5 5), pneumonia (unrelated to P jiroveci; n 5 5), and pyrexia (n 5 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813. (Blood.
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U2 - 10.1182/blood-2017-10-812701
DO - 10.1182/blood-2017-10-812701
M3 - Article
C2 - 29695516
AN - SCOPUS:85050125400
SN - 0006-4971
VL - 132
SP - 293
EP - 306
JO - Blood
JF - Blood
IS - 3
ER -