Stein Mark N, Hussain Maha, Stadler Walter M, Liu Glenn, Tereshchenko Irina V, Goodin Susan, Jeyamohan Chandrika, Kaufman Howard L, Mehnert Janice, DiPaola Robert S
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
University of Michigan, Ann Arbor, MI.
Clin Genitourin Cancer. 2016 Feb;14(1):22-7. doi: 10.1016/j.clgc.2015.09.010. Epub 2015 Sep 21.
In a phase II multicenter study, men with castration sensitive metastatic prostate cancer were treated with AT-101, a small molecule Bcl-2 inhibitor, and androgen deprivation therapy. At the end of 7 cycles of therapy in 55 patients, an undetectable PSA was achieved in 31%. However, the combination did not meet the pre-specified level of activity for further development.
We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer.
Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (≤ 0.2 ng/mL) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients.
A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27.6 ng/dL. Of the 55 patients, 72% had a Gleason score ≥ 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients.
The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination.
在一项II期多中心研究中，去势敏感性转移性前列腺癌男性患者接受了小分子Bcl-2抑制剂AT-101和雄激素剥夺治疗。在55例患者完成7个周期的治疗后，31%的患者前列腺特异性抗原（PSA）检测不到。然而，该联合治疗未达到预先设定的进一步开发所需的活性水平。
我们对去势敏感性转移性前列腺癌男性患者进行了一项II期研究，以检验小分子Bcl-2抑制剂AT-101在开始接受转移性前列腺癌雄激素剥夺治疗（ADT）的患者中具有临床活性这一假设。
纳入计划开始或最近（6周内）开始ADT的转移性前列腺癌患者。在开始口服AT-101（20mg/天，每28天周期服用21天）前6周开始使用促黄体生成素释放激素激动剂和比卡鲁胺进行ADT。研究的主要终点是7.5个月（单独ADT治疗1.5个月加上ADT与AT-101联合治疗6个月）后前列腺特异性抗原（PSA）水平检测不到（≤0.2ng/mL）的患者百分比。为评估染色质结构域解旋酶DNA结合蛋白1（CHD1）与药物敏感性之间的关联，在部分患者亚组中采用共聚焦显微镜荧光原位杂交进行评估。
共纳入55例患者，中位年龄61岁，中位PSA水平为27.6ng/dL。55例患者中，72%的患者Gleason评分≥8。3例患者有内脏转移，其余患者有骨转移或淋巴结转移。31%的患者PSA水平检测不到。在这31例患者中，12例发生严重不良事件，其中7例被认为与研究治疗有关。大多数相关不良事件为胃肠道和神经系统疾病。CHD1评估可行，在少数患者中与治疗敏感性无显著关联。
ADT与AT-101联合治疗未达到该联合方案进一步开发所需的预先设定的活性水平。
