Phase 1b/2 study of ibrutinib and lenalidomide with dose-adjusted EPOCH-R in patients with relapsed/refractory diffuse large B-cell lymphoma

Abstract

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is difficult to cure; non-germinal center B-cell-like (non-GCB) and activated B-cell-like (ABC) DLBCL have worse outcomes than GCB DLBCL. Ibrutinib and lenalidomide are synergistic in vitro in ABC DLBCL and may augment salvage chemotherapy. In part 1 of this phase 1b/2 study (NCT02142049), patients with relapsed/refractory DLBCL received ibrutinib 560 mg and escalating doses of lenalidomide on Days 1-7 with DA-EPOCH-R (Days 1-5) in 21-day cycles. In part 1 (N = 15), the maximum tolerated dose was not reached with lenalidomide 25 mg (recommended part 2 dose [RP2D]); most common grade ≥3 adverse events were anemia (73%) and febrile neutropenia (47%); the overall response rate (ORR) was 40%. At the RP2D (n = 26), ORR was 71% in non-GCB and 64% in ABC. Ibrutinib and lenalidomide with DA-EPOCH-R had a manageable safety profile and antitumor activity in relapsed/refractory DLBCL, especially the non-GCB subtype.

Keywords: Ibrutinib; activated B-cell-like; diffuse large B-cell lymphoma; dose-adjusted EPOCH-R; germinal center B-cell-like; lenalidomide.

Conflict of interest statement

Disclosure statement

W.H.W.: research funding from Pharmacyclics LLC, an AbbVie Company; T.P.: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, Genentech, Seattle Genetics, Curis, Gilead, Bayer, and Incyte; and research funding from Bayer, Incyte, AbbVie, and Pharmacyclics LLC, an AbbVie Company; L.P.: no disclosures; SdV: consultancy/advisory role for Bayer and Verastem; S.C.: consultancy/advisory role for Takeda; A.S.K.: current employee of Amgen and stock/other ownership in Amgen and WindMIL Therapeutics; employee of University of Maryland at the time the study was conducted; D.B.: employee of Pfizer; previous employee of Pharmacyclics LLC, an AbbVie Company; leadership role, stock/other ownership, and research funding from Pfizer and AbbVie; patents/royalties/other intellectual property from AbbVie; and travel accommodations/expenses from Pfizer; D.W.H.: stock/other ownership in and honoraria from AstraZeneca (self); employee of, research funding from, and travel/accommodations/expenses from AstraZeneca (immediate family member); G.W.: patents/royalties/other intellectual property from NanoString; K.K.: employee of Pharmacyclics LLC, an AbbVie Company; and stock/other ownership in AbbVie and Gilead; J.P.: employee of Pharmacyclics LLC, an AbbVie Company; stock/other ownership in AbbVie; J.K.N.: employee of Pharmacyclics LLC, an AbbVie Company; stock/other ownership in AbbVie; L.M.S.: research funding from Pharmacyclics LLC, an AbbVie Company; patents/royalties/other intellectual property for National Institutes of Health and Pharmacyclics LLC, an AbbVie Company.

Figures

Figure 1.

Study schema. DA-EPOCH-R: dose-adjusted cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone, with or without rituximab; IV: intravenous; PO: orally; SC: subcutaneous. aIbrutinib and lenalidomide were administered on days 1–7 of a 21-day cycle for up to six cycles. bDose escalated at doses of 0, 15, 20, and 25 mg (dose levels 1, 2, 3, and 4, respectively). Dose-limiting toxicity was assessed during the first treatment cycle.

Figure 2.

Treatment-emergent adverse events of any grade occurring in ≥30% of the total population in part 1 (A) and in ≥30% of patients treated at the recommended part 2 dose (B). Patients with multiple events for a given preferred term or system organ class are counted once only. Adverse events are sorted by decreasing frequency of preferred term for the total population; the number of patients with each event is shown. RP2D: recommended part 2 dose.

Figure 3.

Best overall tumor response in part 1 (A) and all patients treated at recommended part 2 dose (B). ABC: activated B-cell-like per gene expression profiling; CI: confidence interval; CR: complete response; non-GCB: non-germinal center B-cell-like per immunohistochemistry; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease.

Figure 4.

Progression-free survival (A) and overall survival (B) in patients treated at recommended part 2 dose. ABC: activated B-cell-like per gene expression profiling; non-GCB: non-germinal center B-cell-like per immunohistochemistry. Tick marks represent censored patients.