A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone.
Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone.



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.



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 3+3 design.



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 prostate-specific 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.



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.
Thomas Jefferson University, Philadelphia, Pennsylvania, USA jilin@mfa.gwu.edu.|George Washington University, Washington, D.C., USA.
Jianqing
J
Lin
Thomas Jefferson University, Philadelphia, Pennsylvania, USA jilin@mfa.gwu.edu.
Sheel A
SA
Patel
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Ashwin R
AR
Sama
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Jean H
JH
Hoffman-Censits
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Brooke
B
Kennedy
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Deborah
D
Kilpatrick
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Zhong
Z
Ye
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Hushan
H
Yang
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Zhaomei
Z
Mu
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Benjamin
B
Leiby
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Nancy
N
Lewis
Northwestern University, Evanston, Illinois, USA.
Massimo
M
Cristofanilli
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
William Kevin
WK
Kelly
D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D013739:Testosterone / Q000097:blood
D000736:Androstenes; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D013739:Testosterone; D064096:Aurora Kinase A; C089740:abiraterone; D011241:Prednisone