A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia

Tsuboi, Kosuke; Yokozawa, Toshiya; Sakura, Toru; Watanabe, Takashi; Fujisawa, Shin; Yamauchi, Takahiro; Uike, Naokuni; Ando, Kiyoshi; Kihara, Rika; Tobinai, Kensei; Asou, Hiroya; Hotta, Tomomitsu; Miyawaki, Shuichi

doi:10.1016/j.leukres.2011.04.008

Cited by 48 publications

(44 citation statements)

References 26 publications

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“…In a different trial, 8 out of 32 AML patients had a hematologic response 151 . A similar overall hematologic response rate of 19% was reported in a third study of 16 AML patients 152 . In a phase I/II trial testing AZD1152 versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia, a significant improvement (35.4% vs. 11.5%) in the response was observed in the AZD1152 group.…”

Section: Clinical Trials Of Aurora Kinase Inhibitorssupporting

confidence: 84%

The aurora kinases in cell cycle and leukemia

2014

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The Aurora kinases, which include Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) and meiosis (AURKC). Since their discovery nearly twenty years ago, Aurora kinases have been studied extensively in cell and cancer biology 1. Several early studies found that Aurora kinases are amplified and overexpressed at the transcript and protein level in various malignancies, including several types of leukemia. These discoveries and others provided a rationale for the development of small molecule inhibitors of Aurora kinases as leukemia therapies. The first generation of Aurora kinase inhibitors did not fare well in clinical trials, owing to poor efficacy and high toxicity. However, the creation of second generation, highly selective Aurora kinase inhibitors has increased the enthusiasm for targeting these proteins in leukemia. This review will describe the functions of each Aurora kinase, summarize their involvement in leukemia and discuss inhibitor development and efficacy in leukemia clinical trials.

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Section: Clinical Trials Of Aurora Kinase Inhibitorssupporting

confidence: 84%

The aurora kinases in cell cycle and leukemia

2014

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“…The AEs observed with MSC1992371A (myelosuppression and associated infections, along with diarrhea and mucositis) were similar to those reported with another AKI, barasertib, investigated in a similar clinical setting [5,6]. The similarity of the AEs observed with MSC1992371A (a pan-aurora kinase inhibitor) and barasertib (a selective aurora B inhibitor) indicates that toxicities with this class of compounds are driven predominantly by aurora kinase B inhibition.…”

Section: Discussionsupporting

confidence: 68%

A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies

et al. 2013

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a b s t r a c tA phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n = 36) or on days 1-6 (n = 39) of a 21-day cycle. The maximum tolerated doses were 37 and 28 mg/m 2 /day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses.

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“…78) increases chromosome missegregation rates. In fact, these inhibitors have shown preliminary success in treating primary as well as resistant tumors (79)(80)(81)(82). However, a common dose-limiting adverse effect of many new mitotic drugs is severe bone marrow toxicity and subsequent neutropenia (82).…”

Section: Cin As a Therapeutic Targetmentioning

confidence: 99%

“…In fact, these inhibitors have shown preliminary success in treating primary as well as resistant tumors (79)(80)(81)(82). However, a common dose-limiting adverse effect of many new mitotic drugs is severe bone marrow toxicity and subsequent neutropenia (82). A possible approach to circumvent this toxicity would be to target CIN as an adjuvant therapy to standard treatment, thus limiting the ability of tumors to acquire drug resistance and relapse.…”

Section: Cin As a Therapeutic Targetmentioning

confidence: 99%