Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non–small-cell lung cancer in this phase Ib study.

Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose.

Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non–small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption.

The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.

Bromodomain and extraterminal (BET) proteins are key epigenetic modulators of transcription regulation.1 Their binding to N-acetylated histone tails brings this elongation complex close to the gene promoter region. Several small-molecule inhibitors are being developed that specifically inhibit BET proteins. Birabresib (MK-8628/OTX015) is a selective inhibitor of BRD2, BRD3, and BRD4 (untested activity against BRDT), with 50% inhibitory concentration values from 10 to 19 nmol/L, and inhibits their binding to acetylated histone A4 with 50% inhibitory concentration values of 92 to 112 nmol/L.2 Birabresib has strong in vitro and in vivo antitumor effects in multiple solid tumor xenograft models. In nuclear protein in testis (NUT) midline carcinoma (NMC), defined by a t(15;19)(q14;p13.1) chromosomal translocation that results in a BRD4-NUT fusion protein, inhibition of Ty82 BRD-NUT with birabresib in nude mice leads to 79% tumor growth inhibition.2 These effects were similarly seen in both PC-3 (androgen-resistant) and LNCaP (androgen-sensitive) prostate cancer xenograft models as well as in echinoderm microtubule–associated protein-like 4/anaplastic lymphoma kinase–positive non–small-cell lung cancer (NSCLC) xenograft models.3

In clinical studies of hematologic malignancies, birabresib was safe with manageable adverse effects of thrombocytopenia, GI events, and fatigue, with a recommended phase II dose (RP2D) and schedule of 80 mg 14 days on, 7 days off, and antitumor activity in patients with acute leukemia and diffuse large B-cell lymphoma.4,5 In the current study, we have determined the dose-limiting toxicity (DLT) and RP2D of birabresib given continuously once daily every 3 weeks (cohort A [21 of 21 days]) or for 7 consecutive days every 3 weeks (cohort B [7 of 21 days]).

Study Design

This phase Ib, multicenter, nonrandomized, open-label study of birabresib (OTX015, [OncoEthix, a wholly owned subsidiary of Merck Sharp & Dohme], Lucerne, Switzerland) in patients with select solid tumors was conducted in accordance with good clinical practice. The relevant national authorities provided regulatory approval, and local institutional review boards approved the protocol as appropriate. All study procedures were conducted in accordance with the Declaration of Helsinki. Patients provided written informed consent. The study was sponsored by OncoEthix and registered at

Patients and Treatment

Eligible patients received starting doses of oral 80 mg (cohort A) or 100 mg (cohort B) gelatin capsules under fasting conditions. The preplanned dosing regimens were investigated in parallel cohorts (cohort A, once daily continuously [21 of 21 days]; cohort B, once daily for 7 consecutive days every 3 weeks [7 of 21 days]) using a traditional 3 + 3 dose escalation schedule in patients with NMC, castrate-resistant prostate cancer (CRPC), and NSCLC. Disease-specific expansions were opened after declaration of a maximum tolerated dose (MTD) in each cohort. Eligible patients were age 18 years or older with histologically confirmed NMC (ectopic expression of NUT protein by immunohistochemistry [IHC] and/or detection of BRD-NUT gene translocation by fluorescence in situ hybridization), NSCLC harboring a rearranged ALK gene/fusion protein (fluorescence in situ hybridization or IHC) or KRAS mutation (as defined by any molecular analysis), and CRPC. Patients had Eastern Cooperative Oncology Group performance status ≤ 1; adequate bone marrow, kidney, and liver function; life expectancy ≥ 3 months; and no preceding anticancer therapy within 3 weeks or three or more half-lives for monoclonal antibodies or five or more half-lives for other noncytotoxic agents (whichever was longer). Patients with CRPC maintained ongoing androgen deprivation therapy for the study duration. Patients were excluded if they were unable to swallow study medications, had a previous malignancy within 3 years, were taking concomitant strong CYP3A4-interacting drugs, were pregnant or lactating (women), had known brain metastasis, or had other experimental therapies within 30 days of first treatment dose. The primary objective was occurrence of DLTs in cycle 1 (days 1 to 21) for each regimen. Secondary objectives were safety, efficacy, and pharmacokinetics (PK) of birabresib.


Responses were assessed using RECIST version 1.1 for patients with advanced solid tumors6 or Prostate Cancer Working Group 2 criteria7 for patients with CRPC. Baseline disease assessments were done within 4 weeks before treatment start. Tumor measurements (using the same methodology as at baseline) were conducted every 6 weeks (two cycles), and bone scans were conducted every 12 weeks (four cycles). Best overall response was recorded between the start and end of treatment. National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) were used to grade treatment-emergent adverse events (AEs).8 DLTs, defined as AEs possibly related to birabresib that occurred within the first 21 days (cycle 1), included grade 4 hematologic toxicity or febrile neutropenia, grade 3 neutropenia with infection, grade 3 thrombocytopenia with bleeding or lasting > 7 days, any grade 3 or 4 nonhematologic toxicity (regardless of duration) unless not optimally managed with supportive care (eg, grade 3 vomiting not adequately treated according to antiemetic standard of care), any grade 3 or 4 asymptomatic laboratory abnormality lasting > 7 days (applicable in patients with baseline grade ≤ 1; for patients with grade 2 at baseline, only grade 4 lasting > 7 days considered), any intolerable grade 2 nonhematologic toxicity that resulted in study drug discontinuation or delay > 7 days with or without dose reduction, and treatment delay > 2 weeks or dose reduction requirement for initiating cycle 2. The MTD was defined at the highest dose at which ≤ 33% of patients experienced DLTs during cycle 1. After the MTD was defined, the study was extended to include additional evaluable patients per indication at the MTD. A safety monitoring committee (SMC) of study investigators and the study sponsor reviewed all safety information and made dose escalation decisions by consensus.


Blood samples were collected over six time points in the first 7 hours of cycle 1, day 1, to calculate the PK profile of birabresib (maximum concentration, minimum concentration, maximum time, area under the plasma concentration-time curve, volume of distribution at steady state, half-life, and drug clearance).

Birabresib plasma concentrations were quantified using validated ultra performance liquid chromatography with tandem mass spectrometry detection and analyzed using a nonlinear mixed-effects model.9 PK were described by a one-compartment open model with linear elimination. Descriptive statistics were used to summarize PK parameters. Analyses were conducted using nonlinear mixed-effects modeling10 with Monolix version 4.3 statistical software (

Statistical Analyses

For patients without a DLT in cycle 1, ≥ 85% of the intended cumulative dose of the first 21-day cycle period was required to be evaluable for DLTs. Safety analyses included all patients with one or more doses of study treatment. Efficacy analyses included all patients with two or more completed cycles (6 weeks) of treatment who had undergone baseline assessment and one on-study tumor assessment or who discontinued early as a result of disease progression. Relative dose intensity was determined from actual cumulative dose divided by intended cumulative dose for each patient. Quantitative variables are summarized using descriptive statistics. Data are analyzed according to dose level and regimen for those in dose escalation and according to indication and/or regimen in dose expansion. Mood’s median test was used to calculate the difference between cohorts A and B for time taken to reach platelet nadir.


Between October 31, 2014, and May 17, 2017, 47 patients were enrolled and 46 treated at doses of 80, 100, 120, and 160 mg/d (Table 1); 24 patients were enrolled into cohort A and 22 into cohort B. Of 46 treated patients, 26 (57%) had CRPC, 10 (22%) had NMC, and 10 (22%) had NSCLC. Median age was 60 years (range, 20 to 79 years), with 35% of patients having three or more prior lines of antineoplastic therapy. Treatment discontinuation occurred because of progressive disease in 32 (70%) of 46 patients, other reasons in six (13%), AEs in four (9%), and death not related to study drug in four (9%).


Table 1. Baseline Patient Characteristics


Of 46 patients, 44 (96%) were evaluable for DLT in cohort A and cohort B (22 patients each). Six (13%) patients experienced at least one DLT, all within cohort A (Table 2). In cohort A, no DLTs were observed in the first three patients at the starting dose of 80 mg once daily. However, among evaluable patients, two of three experienced DLTs (intolerable grade 2 anorexia and grade 2 nausea with treatment delay lasting > 7 days; grade 4 thrombocytopenia) at the 100 mg once daily dose. Four of 16 additional patients who experienced DLTs (grade 3 ALT and grade 3 hyperbilirubinemia, one patient; grade 3 thrombocytopenia, one patient; grade 4 thrombocytopenia, two patients) at 80 mg once daily were included at SMC recommendation to gain additional data on safety and preliminary efficacy. The MTD and RP2D occurred at 80 mg once daily on a continuous schedule (cohort A). The parallel discontinuous schedule (cohort B) was evaluated to circumvent DLTs observed during continuous dosing, and no DLTs were seen at any dose level (100 mg, 13 patients; 120 mg, three patients; 160 mg, six patients). On the basis of the incidence of GI toxicities and thrombocytopenia observed in other clinical studies of birabresib,4,5 the SMC decided against escalation beyond the 160-mg dose. As such, the MTD was not reached on the discontinuous schedule.


Table 2. DLT and G3 Toxicities in the Evaluable Population


Overall, 38 patients (83%; 19 patients each in cohorts A and B) had a treatment-related AE, 16 patients (35%; cohort A, 13 patients; cohort B, three patients) had a grade 3 to 4 treatment-related AE, and 10 patients (22%; cohort A, 10 patients; cohort B, no patients) had treatment-related serious AEs (Table 3). Six (13%) of 46 patients (cohort A, five patients; cohort B, one patient) had a nontreatment-related grade 5 AE as a result of cardiac arrest and pulmonary failure (one patient); fatigue (one patient); atrial fibrillation, pleural effusion, pulmonary infection, and dyspnea (one patient); pneumomediastinum (one patient); and general state alteration (two patients). No treatment-related grade 5 AEs occurred. In total, common treatment-related AEs were diarrhea in 17 (37%) of 46 patients, nausea in 18 (39%), decreased appetite in 14 (30%), vomiting in 13 (28%), and thrombocytopenia in 10 (22%). Common treatment-related serious AEs were thrombocytopenia in seven (17%) of 46 patients, diarrhea in 4%, nausea in 4%, hyperbilirubinemia in 2%, elevated ALT in 2%, decreased appetite in 2%, and acute kidney injury in 2%. Asymptomatic factor VII deficiency, previously detected in other clinical studies of birabresib,4,5 was seen in eight patients (17%). Grade 3 treatment-related AEs included thrombocytopenia in five (11%) of 46 patients, elevated ALT in 4%, nausea in 2%, vomiting in 2%, asthenia in 2%, acute kidney injury in 2%, and hyperbilirubinemia in 2%. Grade 4 treatment-related thrombocytopenia was identified in four (17%) of 24 patients in cohort A (three at 80 mg and one at 100 mg once daily) and in zero of 22 patients in cohort B. In three of these patients, the grade 4 thrombocytopenia was identified in cycle 1, with subsequent dose reductions, interruption, or withdrawal. Overall, 18 (39%) of 46 patients had dose reductions or interruptions or treatment withdrawals because of treatment-related grade 2 to 4 AEs. Three patients (7%; all cohort A) discontinued the study because of a treatment-related serious AE. No differences were seen in nonhematologic toxicities between cohorts.


Table 3. Treatment-Related AEs

Treatment Exposure

Examination of platelet kinetics between dosing regimens showed that across cohorts A and B, the thrombocytopenia nadir occurred after a median of 32 days (range, 12 to 211 days) from the start of birabresib exposure (cohort A median, 25.5 days [range, 12 to 211 days]; cohort B median, 36.5 days [range, 12 to 127 days]; P = .14; Appendix Fig A1, online only). Patients received a median of three (interquartile range, 0.3 to 22) 21-day cycles. Sixteen (67%) of 24 patients in cohort A and 13 (59%) of 22 patients in cohort B received up to 12 weeks of treatment. Twelve (50%) of 24 patients in cohort A and 16 (73%) of 22 patients in cohort B had a relative dose intensity of 0.9 to < 1.1. Of 46 treated patients, 18 (39%) experienced treatment-related dose delays (cohort A, 11 patients; cohort B, one patient) or dose reduction (cohort A, no patients; cohort B, one patient) or were withdrawn from the study drug (cohort A, four patients; cohort B, one patient). Reasons for dose reduction/delay were thrombocytopenia in 10 (56%) of 18 patients, asthenia in three (17%), and nausea in three (17%), with seven (39%) of 18 patients requiring multiple delays.

Tumor Response

Of 42 patients evaluable for efficacy, three (7%) had partial response (PR) as a best response and 25 (60%) had stable disease (SD), for a disease control rate of 67% (Table 4). All PRs were reported in patients with NMC who received the 80 mg once daily continuous dose (one PR occurred after cycle 10). In addition, SD with a duration of approximately 3.8 months and 6.0 months occurred in two patients with NSCLC at 100 mg and 160 mg, respectively, with discontinuous dosing, and in two patients with CRPC (3.5 and 7.8 months). Figure 1 shows the kinetics of antitumor activity in cohorts A and B.


Table 4. Summary of Best Overall Response for Evaluable Patients


Analysis of plasma PK parameters in evaluable patients showed that birabresib is absorbed with a median time to peak concentrations ranging from 1.9 to 2.9 hours and a half-life of 3.6 to 5.3 hours (Table 5). Birabresib exposure increased dose proportionately from 80 to 160 mg (Appendix Fig A2, online only). Exposure to birabresib in patients with different tumor types within a dose or regimen was similar, which indicated that the tumor type was not a covariate. Patients with SD or PR as best response did not have favorable PK compared with patients with progressive disease.


Table 5. Plasma Pharmacokinetic Parameters

In this first report to our knowledge of the safety profile of the BET inhibitor birabresib in patients with select solid tumors, the major DLT observed was reversible thrombocytopenia. Additional cumulative nonhematologic toxicities were diarrhea, nausea, anorexia, and fatigue. Decrease in asymptomatic factor VII was observed similar to other reports of birabresib4,5 and potentially related to inhibition of factor VII gene expression.4 Toxic effects were dose dependent in the continuous dosing cohort, with doses at 100 mg once daily being intolerable and two of three patients having DLTs (intolerable grade 2 anorexia and grade 2 nausea lasting > 7 days; grade 4 thrombocytopenia). In the hope of mitigating the cumulative toxicities of continuous dosing, especially with regard to thrombocytopenia, an intermittent schedule was initiated on a 7 days on, 14 days off schedule. This approach reduced the severity of toxic effects, and the MTD was not reached up to 160 mg in heavily pretreated patients who had disease progression on standard therapies. The intermittent scheduling seemed to increase the time to platelet nadir, which potentially allowed for a higher relative dose intensity than continuous dosing (73% v 50%).

Antitumor effects were seen in NMC at 80 mg once daily continuous dosing. However, these responses were short lived, with duration of response ranging from 1.4 to 8.4 months. The clinical activity identified in NMC is of particular interest and supports preclinical work that showed rapid growth arrest in both in vitro and in vivo studies.2,11,12 In the current study, most patients with NMC were eligible on the basis of ectopic expression of NUT protein determined by IHC and, thus, were not universally confirmed to have the BRD4-NUT fusion. However, there is a rationale for BET inhibition in the less common BRD3-NUT13 and NSD3-NUT14 fusions given that they likely have similar chromatin binding activity to BRD415 and that JQ1 (a birabresib analog) has a similar pharmacodynamic profile with either fusion domain.11 Of the nine evaluable patients with NMC, six demonstrated PR or SD in keeping with the growth arrest that can be achieved when interrupting BRD-NUT fusion oncoproteins16-18 and provides proof of concept for BET inhibition in NMC. However, the rapid initial responses are usually transient in nature, which suggests secondary resistance mechanisms that may include restoration of MYC transcription through the WNT pathway or BRD4 phosphorylation16,19-21 and supports the need for synergistic combination studies. Although no formal pharmacodynamic biomarkers were evaluated in the current study, the effects on platelets may serve as markers of biologic activity.

Multiple BET inhibitors currently are in varying stages of development, although to our knowledge, this is the first full publication of BRD inhibition in solid cancers. In keeping with the adverse effect profile of birabresib, a phase I study of GSK525762 in 70 patients (including 17 with NMC) showed common AEs of thrombocytopenia (44%), nausea (40%), and vomiting (29%).22 Clinical activity was seen in 10 patients with NMC, with two patients with PR and four with SD.22 In contrast, a dose-finding study of BAY1238097 in eight patients with advanced solid tumors/non-Hodgkin lymphoma was prematurely terminated in the setting of unacceptable toxicities (grade 3 vomiting, grade 3 headache, grade 3 pain) at below-predicted therapeutic levels.23 In a phase I study of BI 894999, 10 of 28 patients had an elevated troponin T level24 that was potentially related to an off-target effect, a finding that was not seen in the current cohort. Tumor responses were seen with BI 894999 in small bowel adenocarcinoma and esophageal squamous cell cancer, which were not tumor subtypes explored in the current study.

One rationale for BET inhibition in non-NMC solid cancers is that bromodomains are critical for recruiting the transcriptional machinery necessary for oncogenic gene expression.25 Potentially because of its predominantly cytostatic effects and given the limited single-agent activity seen to date in non-NMC tumor types, multiple preclinical combination studies of BET inhibition are being investigated. For example, in ovarian cancer cell lines, when JQ1, a tool compound with BET inhibitory activity, was added to trametinib, synergistic reduction in tumor volume was achieved.26 This is in keeping with other reports in lymphoma where additive cytotoxic effects were demonstrated when BET inhibition was combined with agents such as everolimus, vorinostat, and lenalidomide.27 In CRPC, preclinical studies have shown that BET inhibition could attenuate androgen receptor signaling28 and exhibit enhanced tumor growth inhibition in conjunction with androgen receptor blockade.29 Ongoing combination studies of BET inhibitors with enzalutamide or abiraterone ( identifiers: NCT02607228 and NCT02711956) will clarify the potential for such a strategy. Similarly, preclinical work has identified that JQ1 plays a role in PD-L1 regulation and correlates with increased anti–tumor cytotoxic T cells.30 When JQ1 was combined with PD-1 blockade in a KRAS mutant NSCLC xenograft, synergistic tumor burden reduction was achieved.31 Together, these data highlight the potential of combination therapy for birabresib with standard therapies (androgen receptor inhibitors) or newer agents (immunotherapies, poly [ADP-ribose] polymerase inhibitors) and warrant investigation in future clinical trials.

In conclusion, with BET inhibition with birabresib in select solid tumors, dose proportional exposure is seen with a favorable tolerability profile of reversible and self-limiting thrombocytopenia that requires dose modification. Future evaluations of birabresib need to consider intermittent scheduling to mitigate the potential toxicities of continuous dosing. Clinical activity was observed in patients with NMC, which provides a strong clinical rationale for this targeted approach to this rare entity. Although clinical improvement in other tumor types was demonstrated, given preclinical synergy, combination studies likely are warranted.

© 2018 by American Society of Clinical Oncology

Supported by OncoEthix, a wholly owned subsidiary of Merck Sharp & Dohme and Merck & Co, Kenilworth, NJ.

Presented at the European Organisation for Research and Treatment of Cancer, National Cancer Institute, and American Association for Cancer Research Molecular Targets and Cancer Therapeutics Symposium, Munich, Germany, November 29-December 2, 2016.

Clinical trial information: NCT02259114.

See accompanying article on page 3040

Conception and design: Anastasios Stathis, Jean-Pierre Delord, Solange Peters, Ahmad Awada, Mohamed Bekradda, Susan Perez, Lillian L. Siu, Christophe Massard

Administrative support: Lillian L. Siu

Provision of study materials or patients: Ahmad Awada, Lillian L. Siu

Collection and assembly of data: Jeremy Lewin, Jean-Charles Soria, Anastasios Stathis, Jean-Pierre Delord, Solange Peters, Philippe G. Aftimos, Mohamed Bekradda, Zhen Zeng, Susan Perez, Lillian L. Siu, Christophe Massard

Data analysis and interpretation: Jeremy Lewin, Jean-Pierre Delord, Solange Peters, Ahmad Awada, Philippe G. Aftimos, Keyvan Rezai, Zhen Zeng, Azher Hussain, Susan Perez, Lillian L. Siu, Christophe Massard

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to or

Jeremy Lewin

No relationship to disclose

Jean-Charles Soria

Employment: MedImmune

Stock or Other Ownership: AstraZeneca

Honoraria: AstraZeneca, Roche, Sanofi, Servier, Pierre Fabre, Mersana Therapeutics

Anastasios Stathis

Honoraria: Amgen

Research Funding: Merck Sharp & Dohme (Inst), Pfizer (Inst), Celgene (Inst)

Jean-Pierre Delord

No relationship to disclose

Solange Peters

Honoraria: Roche, Bristol-Myers Squibb, Novartis, Pfizer, MSD, AstraZeneca, Boehringer Ingelheim

Consulting or Advisory Role: Roche, Genentech, Novartis, Bristol-Myers Squibb, Pfizer, MSD, Amgen, AstraZeneca, Janssen Pharmaceuticals, Regeneron Pharmaceuticals

Travel, Accommodations, Expenses: Roche

Ahmad Awada

No relationship to disclose

Philippe G. Aftimos

Honoraria: Amgen

Consulting or Advisory Role: Synthon (Inst), MacroGenics (Inst)

Travel, Accommodations, Expenses: MSD

Mohamed Bekradda

Stock or Other Ownership: OncoEthix

Keyvan Rezai

No relationship to disclose

Zhen Zeng

Employment: Merck

Stock or Other Ownership: Merck

Azher Hussain

Employment: Merck

Stock or Other Ownership: Merck

Susan Perez

Employment: Merck

Stock or Other Ownership: Merck

Lillian L. Siu

Honoraria: Merck

Research Funding: Merck (Inst)

Christophe Massard

Honoraria: Merck

Research Funding: Merck (Inst)


We thank the patients and their families and caregivers, all primary investigators and their site personnel, Eric H. Rubin for supervision of research and critical review of the manuscript, Anilkumar Anksapur for help with statistical analyses, and Luana Atherly-Henderson (Merck & Co) for assistance with manuscript editing funded by Merck & Co.

1. Filippakopoulos P, Knapp S: Targeting bromodomains: Epigenetic readers of lysine acetylation. Nat Rev Drug Discov 13:337-356, 2014 Crossref, MedlineGoogle Scholar
2. Noel JK, Iwata K, Ooike S, et al: Development of the BET bromodomain inhibitor OTX015. Mol Cancer Ther 12:C244, 2013 Google Scholar
3. Riveiro M, Astorgues-Xerri L, Ijaz N, et al: 564 OTX015, a novel BET-BRD inhibitor is active in non-small-cell lung cancer cell (NSCLC) lines harboring different oncogenic mutations. Eur J Cancer 50:182, 2014 CrossrefGoogle Scholar
4. Amorim S, Stathis A, Gleeson M, et al: Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: A dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol 3:e196-e204, 2016 Crossref, MedlineGoogle Scholar
5. Berthon C, Raffoux E, Thomas X, et al: Bromodomain inhibitor OTX015 in patients with acute leukaemia: A dose-escalation, phase 1 study. Lancet Haematol 3:e186-e195, 2016 Crossref, MedlineGoogle Scholar
6. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009 Crossref, MedlineGoogle Scholar
7. Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148-1159, 2008 LinkGoogle Scholar
8. US Department of Health and Human Services; National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Bethesda, MD, National Cancer Institute, 2016 Google Scholar
9. Odore E, Lokiec F, Weill S, et al: Development and validation of an UPLC-MS/MS method for quantitative analysis of OTX015 in human plasma samples. Anal Methods 6:9108-9115, 2014 CrossrefGoogle Scholar
10. Odore E, Lokiec F, Cvitkovic E, et al: Phase I population pharmacokinetic assessment of the oral bromodomain inhibitor OTX015 in patients with haematologic malignancies. Clin Pharmacokinet 55:397-405, 2016 Crossref, MedlineGoogle Scholar
11. Filippakopoulos P, Qi J, Picaud S, et al: Selective inhibition of BET bromodomains. Nature 468:1067-1073, 2010 Crossref, MedlineGoogle Scholar
12. French CA, Miyoshi I, Kubonishi I, et al: BRD4-NUT fusion oncogene: A novel mechanism in aggressive carcinoma. Cancer Res 63:304-307, 2003 MedlineGoogle Scholar
13. French CA, Ramirez CL, Kolmakova J, et al: BRD-NUT oncoproteins: A family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27:2237-2242, 2008 Crossref, MedlineGoogle Scholar
14. French CA, Rahman S, Walsh EM, et al: NSD3-NUT fusion oncoprotein in NUT midline carcinoma: Implications for a novel oncogenic mechanism. Cancer Discov 4:928-941, 2014 Crossref, MedlineGoogle Scholar
15. Alekseyenko AA, Walsh EM, Wang X, et al: The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains. Genes Dev 29:1507-1523, 2015 Crossref, MedlineGoogle Scholar
16. Doroshow DB, Eder JP, LoRusso PM: BET inhibitors: A novel epigenetic approach. Ann Oncol 28:1776-1787, 2017 Crossref, MedlineGoogle Scholar
17. Shapiro GI, Dowlati A, LoRusso PM, et al: Clinical efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC). Mol Cancer Ther 14:A49, 2015 Google Scholar
18. Stathis A, Zucca E, Bekradda M, et al: Clinical response of carcinomas harboring the BRD4–NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov 6:492-500, 2016 Crossref, MedlineGoogle Scholar
19. Fong CY, Gilan O, Lam EY, et al: BET inhibitor resistance emerges from leukaemia stem cells. Nature 525:538-542, 2015 Crossref, MedlineGoogle Scholar
20. Rathert P, Roth M, Neumann T, et al: Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525:543-547, 2015 Crossref, MedlineGoogle Scholar
21. Shu S, Lin CY, He HH, et al: Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529:413-417, 2016 Crossref, MedlineGoogle Scholar
22. O’Dwyer PJ, Piha-Paul SA, French C, et al: GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: Results from part 1 of a phase I/II open-label single-agent study in patients with NUT midline carcinoma (N MC) and other cancers. Mol Cancer Ther 15:CT014, 2016 Google Scholar
23. Postel-Vinay S, Herbschleb K, Massard C, et al: First-in-human phase I dose escalation study of the bromodomain and extra-terminal motif (BET) inhibitor BAY 1238097 in subjects with advanced malignancies. Eur J Cancer 69:S7-S8, 2016 CrossrefGoogle Scholar
24. Aftimos PG, Bechter O, Awada A, et al: Phase I first-in-man trial of a novel bromodomain and extra-terminal domain (BET) inhibitor (BI 894999) in patients (Pts) with advanced solid tumors. J Clin Oncol 35, 2017 (suppl; abstr 2504) Google Scholar
25. von Schaper E: Roche bets on bromodomains. Nat Biotechnol 34:361-362, 2016 Crossref, MedlineGoogle Scholar
26. Jing Y, Zhang Z, Ma P, et al: Concomitant BET and MAPK blockade for effective treatment of ovarian cancer. Oncotarget 7:2545-2554, 2016 Crossref, MedlineGoogle Scholar
27. Boi M, Gaudio E, Bonetti P, et al: The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res 21:1628-1638, 2015 Crossref, MedlineGoogle Scholar
28. Asangani IA, Dommeti VL, Wang X, et al: Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510:278-282, 2014 Crossref, MedlineGoogle Scholar
29. Asangani IA, Wilder-Romans K, Dommeti VL, et al: BET bromodomain inhibitors enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Mol Cancer Res 14:324-331, 2016 Crossref, MedlineGoogle Scholar
30. Zhu H, Bengsch F, Svoronos N, et al: BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Reports 16:2829-2837, 2016 Crossref, MedlineGoogle Scholar
31. Shimamura T, Chen Z, Soucheray M, et al: Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Clin Cancer Res 19:6183-6192, 2013 Crossref, MedlineGoogle Scholar



DOI: 10.1200/JCO.2018.78.2292 Journal of Clinical Oncology 36, no. 30 (October 20, 2018) 3007-3014.

Published online May 07, 2018.

PMID: 29733771

ASCO Career Center