TY - JOUR
T1 - A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone for patientswithmetastatic castration-resistant prostate cancer progressing on abiraterone
AU - Lin, Jianqing
AU - Patel, Sheel A.
AU - Sama, Ashwin R.
AU - Hoffman-Censits, Jean H.
AU - Kennedy, Brooke
AU - Kilpatrick, Deborah
AU - Ye, Zhong
AU - Yang, Hushan
AU - Mu, Zhaomei
AU - Leiby, Benjamin
AU - Lewis, Nancy
AU - Cristofanilli, Massimo
AU - Kelly, William Kevin
N1 - Publisher Copyright:
© AlphaMed Press 2016.
PY - 2016/11
Y1 - 2016/11
N2 - Background. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. Methods. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1–7 every 21 days) per standard 313 design. Results. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostatespecific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. Conclusion. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.
AB - Background. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. Methods. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1–7 every 21 days) per standard 313 design. Results. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostatespecific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. Conclusion. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.
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U2 - 10.1634/theoncologist.2016-0297
DO - 10.1634/theoncologist.2016-0297
M3 - Article
C2 - 28178640
AN - SCOPUS:84995451106
VL - 21
SP - 1296
EP - 1297
JO - Oncologist
JF - Oncologist
SN - 1083-7159
IS - 11
ER -