A phase 1 study of the pan-bromodomain and extraterminal inhibitor mivebresib (ABBV-075) alone or in combination with venetoclax in patients with relapsed/refractory acute myeloid leukemia

Abstract

Background: Acute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach.

Methods: In this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg).

Results: Forty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure.

Conclusions: Mivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML.

Lay summary: Mivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia.

Keywords: ABBV-075; acute myeloid leukemia; bromodomain and extraterminal domain protein; mivebresib; phase 1 clinical trial.

Conflict of interest statement

Gautam Borthakur reports research support from AbbVie, Incyte, Janssen, GlaxoSmithKline, Cyclacel, and BioLine Rx; and personal consulting or advisory fees from NKarta, PTC Therapeutics, and BioLine Rx. Olatoyosi Odenike reports personal consulting or advisory fees from AbbVie, Impact Biomedicines, and Celgene; and research funding from Celgene, Incyte, Astex Pharmaceuticals, NS Pharma, AbbVie, Gilead Sciences, Janssen Oncology, OncoTherapy Science, Agios, AstraZeneca, and Aprea. Ibrahim Aldoss reports honoraria from Helocyte, Jazz Pharmaceuticals, and Agios; personal consulting or advisory fees from AbbVie, Helocyte, Agios, and Kite (a Gilead Company); speaker's fees from Jazz Pharmaceuticals; and travel accommodations and expenses from AbbVie, Helocyte, Jazz Pharmaceuticals, and Agios. David A. Rizzieri reports personal consulting/advisory fees or honoraria from Novartis, Kite (a Gilead Company), Gilead Sciences, Incyte, Pfizer, TEVA, Seagen, and Amgen; and speaker's fees from Incyte, Seagen, and Gilead Sciences. Thomas Prebet reports personal consulting or advisory fees from Genentech, Tetraphase, and Jazz Pharmaceuticals; and research support from Agios, Bristol‐Myers Squibb, Jazz Pharmaceuticals, and Boehringer Ingelheim. Chris Chen, Relja Popovic, Dimple A. Modi, Rujuta H. Joshi, and Johannes E. Wolff are employees of AbbVie and may own stock in the company; they report travel accommodations and expenses from AbbVie. Brian A. Jon​as reports institutional grants and research support from 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, Esanex, F. Hoffmann‐La Roche, Forma, Genentech/Roche, GlycoMimetics, Hanmi, Incyte, Jazz Pharmaceuticals, LP Therapeutics, Pfizer, Pharmacyclics, and Sigma Tau; personal consulting or advisory fees from AbbVie, Amgen, Celgene, Genentech/Roche, GlycoMimetics, Jazz Pharmaceuticals, Takeda, Tolero, and Treadwell; and travel expenses from AbbVie, Amgen, and GlycoMimetics.

© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

Figures

Figure 1

The best percentage change in the bone marrow blast count from baseline is illustrated. A linear regression model was fitted with the response variable percent change in blast count. Paired symbols (triangles, squares, diamonds, crosses, and stars) designate bars for each of the 5 patients who switched from the mivebresib monotherapy (Mono) arm to the mivebresib combined with venetoclax (Combo) arm (switchers; ie, their response on monotherapy and their subsequent response on combination therapy).

Figure 2

An analysis of overall survival is illustrated for patients with relapsed/refractory acute myeloid leukemia who received mivebresib monotherapy (Mono) and mivebresib combined with venetoclax (Combo). Kaplan‐Meier survival curves were used to determine the overall survival of patients in the Mono cohort (n = 19) and the Combo cohort (n = 25).

Figure 3

Pharmacokinetics profiles of mivebresib (ABBV‐075) are charted in patients with relapsed/refractory acute myeloid leukemia who received (A) mivebresib monotherapy (Mono) and (B) mivebresib combined with venetoclax (Combo) on cycle 1 day 1 (C1D1) and cycle 1 day 8 (C1D8). Dosing schedules and concentration time profiles with standard error bars are shown. QD indicates daily.

Figure 4

The correlation between drug exposure (maximum observed plasma concentration [Cmax]) and gene modulation at 6 hours posttreatment with mivebresib monotherapy on cycle 1 day 1 in peripheral blood from patients with relapsed/refractory acute myeloid leukemia is illustrated. Linear regression was used to determine the correlation (R2) between the cycle 1 day 1 Cmax and the biomarker percent change from baseline at 6 hours postdosing. The R2 and P values are shown. The number of patients at each dose was n = 3 at 1 mg, n = 4 at 1.5 mg, and n = 5 at 2 mg.

Figure 5

Molecular biomarkers of sensitivity and resistance to (A) mivebresib monotherapy (MIV‐mono) and (B) mivebresib in combination with venetoclax (MIV‐Ven) are illustrated. Baseline molecular markers that differentiate each patient (Pt.) with and without biologic activity in the MIV‐mono and MIV‐Ven cohorts are listed. The mutations reported were detected in blood and/or bone marrow samples using the TruSight Myeloid Sequencing Panel (Illumina) or institution‐specific next‐generation sequencing–based myeloid panels. *Note that biologic activity was defined as any reduction in the bone marrow blast count while on MIV‐mono or MIV‐Ven therapy. CR indicates complete response; CRi, complete remission with incomplete blood count recovery; MLFS, morphologic leukemia‐free state.