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.

Conflict of interest statement

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.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Study design. *Reduced to INCB040093 100 mg twice daily (BID) and itacitinib 300 mg once daily (QD) in expansion cohorts based on safety data beyond the DLT observation period (represents RP2D for the combination). †As confirmed by immunohistochemistry. GCB, germinal center B-cell-like; RP2D, recommended phase 2 dose.

Figure 2.

Steady-state plasma concentrations of the PI3Kδ inhibitor INCB040093. (A) Patients receiving multiple doses of INCB040093 monotherapy in Part 1. (B) Patients receiving multiple doses of INCB040093 combined with the JAK1 inhibitor itacitinib in Part 2. IC90, 90% inhibitory concentration; SE, standard error.

Figure 3.

PI3Kδ signaling inhibition after treatment with the PI3Kδ inhibitor INCB040093. PI3Kδ and JAK1 inhibition as measured using an in vitro assay from whole blood samples (mononuclear cells) obtained on day 15 of cycle 1 from patients receiving INCB040093 at doses of (A) 100 mg BID, (B) 150 mg BID, and (C) 300 mg QD. No target inhibition was observed predose.

Figure 4.

Best percentage change from baseline in target lesion size. (A) Patients receiving the PI3Kδ inhibitor INCB040093 alone. (B) Patients receiving INCB040093 combined with the JAK1 inhibitor itacitinib. Included are patients with data available for best percentage change from baseline in target lesion size (monotherapy, n = 45; combination therapy, n = 55). The upper dotted line corresponds to criteria for PD (at least 50% increase) and lower to PR (at least 50% decrease). PD indicates PD or relapsed disease (after CR). Patients with 18F-FDG–avid lymphoma who were PET-positive at baseline could achieve a CR without complete resolution of the target lesion if the lesion became PET-negative per the Revised Response Criteria for Malignant Lymphoma.23 *Patient was not evaluable for response; the target lesion size was from an assessment, which was 7 days after starting treatment; no other on-study assessment was available. †Best percentage change from baseline in target lesion size >100%.

Figure 5.

Best percentage change from baseline in target lesion size in patients with cHL receiving therapy with PI3Kδ inhibitor INCB040093 alone or in combination with JAK1 inhibitor itacitinib. Included are patients with data available for best percentage change from baseline in target lesion size (n = 37 [monotherapy, n = 17; combination therapy, n = 20]). The upper dotted line corresponds to criteria for PD (at least 50% increase) and lower to PR (at least 50% decrease). PD indicates PD or relapsed disease (after CR). Patients with 18F-FDG-avid lymphoma who were PET-positive at baseline could achieve a CR without complete resolution of the target lesion if the lesion became PET-negative per the Revised Response Criteria for Malignant Lymphoma. *Best percentage change from baseline in target lesion size >100%. †Patients who discontinued INCB040093 monotherapy and re-enrolled into the study to receive combination therapy. ‡Patients who had previously received INCB040093 monotherapy.