Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma.

Abstract

Because both phosphatidylinositol 3-kinase δ (PI3Kδ) 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 PI3Kδ 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 = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + 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) and pyrexia (n = 4), and with combination Pneumocystis jiroveci pneumonia (n = 5), pneumonia (unrelated to P jiroveci; n = 5), and pyrexia (n = 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.

• Authors: 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
• Journal: Blood (Blood) Vol. 132 Issue 3 Pg. 293-306 (07 19 2018) ISSN: 1528-0020 [Electronic] United States
• PMID: 29695516 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Protein Kinase Inhibitors
• Class I Phosphatidylinositol 3-Kinases
• PIK3CD protein, human
• JAK1 protein, human
• Janus Kinase 1

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors)
• Combined Modality Therapy
• Female
• Humans
• Janus Kinase 1 (antagonists & inhibitors)
• Lymphoma, B-Cell (diagnostic imaging, drug therapy, metabolism, pathology)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics)
• Research Design
• Treatment Outcome
• Young Adult