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

Jianqing Lin, Sheel A Patel, Ashwin R Sama, Jean H Hoffman-Censits, Brooke Kennedy, Deborah Kilpatrick, Zhong Ye, Hushan Yang, Zhaomei Mu, Benjamin Leiby, Nancy Lewis, Massimo Cristofanilli, William Kevin Kelly, Jianqing Lin, Sheel A Patel, Ashwin R Sama, Jean H Hoffman-Censits, Brooke Kennedy, Deborah Kilpatrick, Zhong Ye, Hushan Yang, Zhaomei Mu, Benjamin Leiby, Nancy Lewis, Massimo Cristofanilli, William Kevin Kelly

Abstract

Lessons learned: 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.

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 3+3 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 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.

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.

Trial registration: ClinicalTrials.gov NCT01848067.

©AlphaMed Press; the data published online to support this summary is the property of the authors.

Figures

Figure 1.
Figure 1.
Effects of alisertib on androgen synthesis. (A): DHEA levels during the study treatment. (B): Total testosterone levels during the study treatment. Abbreviations: C2, cycle 2; DHEA, dehydroepiandrosterone.

References

    1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.
    1. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–148.
    1. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–1038.
    1. Dees EC, Cohen RB, von Mehren M, et al. Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: Safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res. 2012;18:4775–4784.
    1. Melichar B, Adenis A, Lockhart AC, et al. 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. Lancet Oncol. 2015;16:395–405.
    1. Stein ME, Bernstein Z, Abacioglu U, et al. Small cell (neuroendocrine) carcinoma of the prostate: etiology, diagnosis, prognosis, and therapeutic implications—a retrospective study of 30 patients from the rare cancer network. Am J Med Sci. 2008;336:478–488.
    1. Flechon A, Pouessel D, Ferlay C, et al. Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: Results of the French Genito-Urinary Tumor Group (GETUG) P01 trial. Ann Oncol. 2011;22:2476–2481.
    1. Berruti A, Dogliotti L, Mosca A, et al. Potential clinical value of circulating chromogranin A in patients with prostate carcinoma. Ann Oncol. 2001;12(suppl 2):S153–S157.
    1. Sarkar D, Singh SK, Mandal AK, et al. Plasma chromogranin A: Clinical implications in patients with castrate resistant prostate cancer receiving docetaxel chemotherapy. Cancer Biomark. 2010;8:81–87.
    1. Loriot Y, Massard C, Gross-Goupil M, et al. Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: A prospective study evaluating also neuroendocrine features. Ann Oncol. 2009;20:703–708.
    1. Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1:487–495.
    1. Aparicio A, Tzelepi V, Araujo JC, et al. Neuroendocrine prostate cancer xenografts with large-cell and small-cell features derived from a single patient’s tumor: Morphological, immunohistochemical, and gene expression profiles. Prostate. 2011;71:846–856.
    1. Buschhorn HM, Klein RR, Chambers SM, et al. Aurora-A over-expression in high-grade PIN lesions and prostate cancer. Prostate. 2005;64:341–346.
    1. Furukawa J, Miyake H, Takenaka A, et al. Persistent expression of Aurora-A after neoadjuvant hormonal therapy as a predictor of a poor clinical outcome in patients undergoing radical prostatectomy for prostate cancer. BJU Int. 2007;100:310–314.
    1. Shu SK, Liu Q, Coppola D, et al. Phosphorylation and activation of androgen receptor by Aurora-A. J Biol Chem. 2010;285:33045–33053.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit