Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study

Melichar, Bohuslav; Adenis, Antoine; Lockhart, A. Craig; Bennouna, Jaafar; Dees, E. Claire; Kayaleh, Omar; Obermannová, Radka; DeMichele, Angela; Zatloukal, Petr; Zhang, Bin; Ullmann, Claudio Dansky; Schusterbauer, Claudia

doi:10.1016/s1470-2045(15)70051-3

Cited by 214 publications

(196 citation statements)

References 29 publications

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“…In a phase I/II trial of Alisertib in refractory solid tumours, alisertib demonstrated single agent activity with an ORR of 21% (n = 48) in the relapsed SCLC subgroups of patients, considerably higher than the 4% ORR observed in patients with NSCLC. Responses were observed in both platinum sensitive (7/10) and platinum refractory disease (3/10) with an overall PFS of 2.1 months [70]. However 43% of patients had serious drug-related adverse events.…”

Section: Alisertibmentioning

confidence: 99%

Targeting DNA damage in SCLC

et al. 2017

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A B S T R A C TSCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's.The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints.Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy.This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.

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Section: Alisertibmentioning

confidence: 99%

Targeting DNA damage in SCLC

et al. 2017

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“…The recommended dose of alisertib for clinical development as a single agent in Western patient populations is 50 mg BID administered for 7 days in 21-day cycles [1][2][3]. This dose and schedule has been used in multiple Phase 2 clinical studies in solid tumor and hematologic malignancies, with clinical antitumor activity observed in small cell lung cancer, breast cancer, head and neck cancer, gastroesophageal adenocarcinoma, ovarian cancer, and various hematologic malignancies [4][5][6][7]. Alisertib has also demonstrated antitumor activity in Phase 2 studies in ovarian cancer [7] and small cell lung cancer [8] at a dose of 40 mg BID administered on Days 1-3, 8-10, 15-17 in combination with weekly paclitaxel (60 mg/m 2 on Days 1, 8 and 15) in 28-day cycles.…”

Section: Introductionmentioning

confidence: 99%

“…This dose and schedule has been used in multiple Phase 2 clinical studies in solid tumor and hematologic malignancies, with clinical antitumor activity observed in small cell lung cancer, breast cancer, head and neck cancer, gastroesophageal adenocarcinoma, ovarian cancer, and various hematologic malignancies [4][5][6][7]. Alisertib has also demonstrated antitumor activity in Phase 2 studies in ovarian cancer [7] and small cell lung cancer [8] at a dose of 40 mg BID administered on Days 1-3, 8-10, 15-17 in combination with weekly paclitaxel (60 mg/m 2 on Days 1, 8 and 15) in 28-day cycles. Identification of further appropriate combination partners and sensitive patient populations is anticipated to ensure that an acceptable risk/benefit profile can be achieved.…”

Section: Introductionmentioning

confidence: 99%

Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies

et al. 2017

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Summary Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC 0-inf ) and maximum concentrations (C max ) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC 0-inf and C max in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC 0-inf and C max in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC 0-inf and C max in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.

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“…Despite our patient's excellent response, the course of the malignancy is such that he will likely relapse. While there is no effective second-line therapy established currently, novel agents being investigated in patients with neuroendocrine prostate cancer, such as aurora kinase A (AURKA) and poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors, might have promising activity in this patient population whose therapeutic options are limited [12][13][14][15].…”

Section: Resultsmentioning

confidence: 99%