Phase 1 study of the PI3Kd inhibitor INCB040093 6 JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Tycel J. Phillips, Andres Forero-Torres, Taimur Sher, Catherine S. Diefenbach, Patrick Johnston, Moshe Talpaz, Jennifer Pulini, Li Zhou, Peggy Scherle, Xuejun Chen, Paul M. Barr

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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. 2018;132(3):293-306)

Original languageEnglish (US)
Pages (from-to)293-306
Number of pages14
JournalBlood
Volume132
Issue number3
DOIs
StatePublished - Jul 19 2018

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Phillips, T. J., Forero-Torres, A., Sher, T., Diefenbach, C. S., Johnston, P., Talpaz, M., Pulini, J., Zhou, L., Scherle, P., Chen, X., & Barr, P. M. (2018). Phase 1 study of the PI3Kd inhibitor INCB040093 6 JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma. Blood, 132(3), 293-306. https://doi.org/10.1182/blood-2017-10-812701