A phase Ib trial with MK-8628/OTX015, a small molecule inhibitor of bromodomain (BRD) and extra-terminal (BET) proteins, in patients with selected advanced solid tumors

Massard, C.; Soria, Jean Charles; Stathis, Anastasios; Delord, Jean Pierre; Awada, A.; Peters, Stefan O.; Lewin, Jeremy; Bekradda, M.; Rezai, Keyvan; Zeng, Zhi; Azher, H.; Perez, Susan; Siu, L.

doi:10.1016/s0959-8049(16)32609-0

Cited by 20 publications

(16 citation statements)

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“…Following the phase I study in hematologic malignancies, OTX015 was subsequently evaluated in a phase I study in patients with selected solid tumors, including patients with NUT carcinoma. In a preliminary report of this study, among 10 patients with NUT carcinoma, 3 patients achieved a partial response (65).…”

Section: Nut Carcinomamentioning

confidence: 77%

“…Overall, OTX015 was well tolerated, and the toxicities were reversible with treatment interruptions. The favorable safety profile of OTX015 was confirmed in the phase I trial in patients with solid tumors (65). Thrombocytopenia, fatigue, gastrointestinal symptoms, and hyperbilirubinemia are among side effects also reported in patients treated with other BET inhibitors (62,66,67), although the results of these trials are currently preliminary and reported only in abstract form.…”

Section: Adverse Eventsmentioning

confidence: 91%

“…Among 46 patients treated (26 CRPC, 10 NUT carcinoma, 9 KRASmutated, and 1 ALK-positive NSCLC), 4 patients had a partial response (including the 3 patients with NUT carcinoma and 1 patient with CRPC). In addition, prolonged stable disease was observed in 5 patients with CRPC (4-8 months) and 2 patients with KRAS-mutated NSCLC (65).…”

Section: Other Solid Tumorsmentioning

confidence: 98%

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BET Proteins as Targets for Anticancer Treatment

2018

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Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. Over the last years, several BET inhibitors have been developed and clinically tested. Results from the first clinical trials show limited single-agent activity in a small subset of patients with hematologic malignancies and in NUT carcinoma. Adverse events have been observed and may limit treatment compliance. Here, we review the preclinical rationale for targeting BET proteins in cancer and the preliminary results from clinical trials, and outline future directions for the use of BET inhibitors as antitumor agents. BET inhibitors represent a new class of anticancer agents. Results from the first clinical trials confirm the antitumor potential of BET inhibitors, but their efficacy as single agents seems to be limited. Based on preclinical data, combination therapies with other anticancer agents and the development of a new generation of compounds may open new possibilities for targeting BET proteins as effective anticancer strategies.

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Section: Nut Carcinomamentioning

confidence: 77%

Section: Adverse Eventsmentioning

confidence: 91%

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BET Proteins as Targets for Anticancer Treatment

2018

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“…Initial reports revealed significant doselimiting toxicities (DLTs) of drugs in Phase I. Best reported are the DLTs of MK‐8268/OTX‐015, CPI‐0610, RO6870810/TEN‐010, BAY1238097 and GSK525762 . Most of them showed similar DLTs including headache, vomiting, diarrhea, fatigue, anorexia, dysgeusia, thrombocytopenia.…”

Section: Clinical Trialsmentioning

confidence: 99%

Bromodomain Drug Discovery – the Past, the Present, and the Future

Pervaiz

Mishra

Günther

2018

The Chemical Record

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With the bromodomain (BRD) inhibitor JQ1, a remarkable success story of BRD4 as a novel drug target has been set off that yielded many anti‐cancer drugs that are now in clinical trials. But not all of the great prospects of BRDs as drug targets may become true. First evaluations of ongoing clinical trials revealed that treatment with BET‐inhibitors can be accompanied with significant toxic side effects and the validation of the therapeutic benefit of BET‐inhibitors compared to existing therapies is still pending. New strategies that may overcome possible obstacles in BRD drug discovery include combination therapies with other agents, dual target inhibitors, and proteolysis targeting chimeras (PROTACs). Furthermore, non‐BET proteins seem promising drug targets as well. Most recently, BRDs have been identified as putative targets to treat parasitic diseases such as malaria. Milestones in BRD drug discovery are reviewed and promising new developments are evaluated.

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“…9,10 Association to disease has fuelled great interest in the field to develop small molecule BET inhibitors, many of which are in the clinic. [11][12][13][14] Many BET inhibitors include a triazolodiazepine scaffold, including JQ1 (ref. 15) and I-BET762 (ref.…”

mentioning

confidence: 99%