Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study

被引：849

作者：

Scher, Howard I. ^{[1
]}

Beer, Tomasz M. ^{[6
]}

Higano, Celestia S. ^{[8
]}

Anand, Aseem

Taplin, Mary-Ellen ^{[9
]}

Efstathiou, Eleni ^{[10
]}

Rathkopf, Dana

Shelkey, Julia

Yu, Evan Y. ^{[8
]}

Alumkal, Joshi ^{[6
]}

Hung, David ^{[11
]}

Hirmand, Mohammad ^{[11
]}

Seely, Lynn ^{[11
]}

Morris, Michael J.

Danila, Daniel C.

Humm, John ^{[3
]}

Larson, Steve ^{[2
]}

Fleisher, Martin ^{[4
]}

Sawyers, Charles L. ^{[5
,7
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, Sidney Kimmel Ctr Prostate & Urol Canc, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Nucl Med Serv, Dept Med Imaging, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Clin Labs, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[6] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[7] Howard Hughes Med Inst, Chevy Chase, MD USA

[8] Univ Washington, Seattle, WA 98195 USA

[9] Dana Farber Canc Inst, Boston, MA 02115 USA

[10] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[11] Medivation, San Francisco, CA USA

来源：

LANCET | 2010年 / 375卷 / 9724期

关键词：

CIRCULATING TUMOR-CELLS; HORMONAL-THERAPY; CLINICAL-TRIALS; SURVIVAL; PROGRESSION; MUTATIONS; IMATINIB; GENE; TESTOSTERONE; ANTIANDROGEN;

D O I：

10.1016/S0140-6736(10)60172-9

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. Methods This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718. Findings We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased F-18-fluoro-5 alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34 not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction. Interpretation We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease.

引用

页码：1437 / 1446

页数：10

共 30 条

[1] Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation [J].