Development of Drugs That Target Prostate Cancer

随着两项具有里程碑意义的随机试验的发表，多西他赛化疗现在是转移性CRPC男性的标准治疗方案。然而，这种治疗的益处是有限的。目前的试验重点是通过将多西紫杉醇与新型生物制剂联合使用来提高疗效。一些新的基于多西他赛的组合正在评估中，多西他赛与血管生成抑制剂的组合已经发现了有希望的结果。我们正在尝试开发新的药剂来改变癌症的生物学特性。为了实现这一目标，我们已经开始与一家独特的计算化学公司合作，设计能够消除癌症发生、进展和转移过程中关键分子靶点的化合物。这些研究才刚刚开始，但可以提供有价值的新药物。根据先前的实验表明，微管活性药物与酮康唑联合在体外的疗效增加，当在多种前列腺癌细胞系中进行测试时，我们启动了酮康唑联合每周多西紫杉醇治疗雄激素非依赖性前列腺癌（AIPC）患者的I期试验。本研究的主要目的是确定副作用概况和MTD。考虑到可能的药物-药物相互作用，多西他赛和酮康唑的起始剂量分别为5mg /m2和1200mg /d。多西紫杉醇剂量为10mg /m2时，观察到明显的肝毒性。给药方案改为酮康唑600 mg/d，多西他赛10 mg/m2。迄今为止，共有30名患者接受了这种联合治疗，目前正在进行药代动力学分析。一项随机II期试验已经完成了72例进展性AIPC转移到骨的患者，酮康唑联合阿仑膦酸钠与酮康唑单独使用。AIPC患者单纯KT/H与KT/H + AL治疗的有效率、无进展生存期或总生存期无统计学差异。与单独使用KT/H治疗相比，在KT/H治疗中加入AL可能会增加反应持续时间，并具有可接受的安全性。然而，AL的加入对AIPC患者的生存没有好处。最近，一项用于AIPC的II期研究已经完成。该药治疗伴有疲劳和胃肠道毒性。未观察到抗前列腺癌的显著临床活性。在这一人群中，不值得进一步的单药治疗研究。索拉非尼治疗去癌抵抗性前列腺癌（CRPC）：为了确定索拉非尼是否与4个月无进展生存率的提高相关，仅使用放射学和临床标准，我们在转移性CRPC患者中进行了2期试验。次要终点包括药代动力学、毒性分析和总生存期。该研究为开放标签、II期、两阶段设计，重点关注第二阶段的结果，因为在完成第一阶段后修改了进展标准。索拉非尼的剂量为400毫克，每天口服两次，28天为一个周期。每4周进行一次临床和实验室评估，每8周进行一次x线扫描。第二阶段累计24例患者；中位（范围）年龄66岁（49-85岁），研究中前列腺特异性抗原水平68.45 (5.8-995)ng/mL， Gleason评分8(6-9)，东部肿瘤合作组状态1（17例）。在24名患者中，21名患者之前曾接受过多西紫杉醇化疗。所有患者均有骨转移，单独（11例）或合并软组织疾病（13例）。一名患者有部分反应；10例患者病情稳定（中位持续时间18周，范围15-48周）。中位潜在随访期为27.2个月，中位无进展生存期为3.7个月，中位总生存期为18.0个月。在整个试验中，46名患者的中位生存期为18.3个月。最常见的毒性包括手足皮肤反应（9例2级，3例3级）、皮疹、肝功能检查异常和疲劳。索拉非尼作为转移性去势抵抗性前列腺癌的二线治疗具有中等活性。间歇性雄激素消融治疗雄激素依赖性前列腺癌的沙利度胺与安慰剂：我们确定沙利度胺是否可以延长有限雄激素剥夺治疗的生化复发性前列腺癌患者的无进展生存期。共有159名患者参加了一项双盲随机试验，以确定沙利度胺是否可以提高促性腺激素释放激素激动剂对前列腺癌原发性最终治疗后前列腺特异性抗原升高的激素应答患者的疗效。患者被随机分配到6个月的促性腺激素释放激素激动剂，随后是每天200毫克口服沙利度胺或安慰剂（口服A期）。在前列腺特异性抗原进展时，又重新开始使用促性腺激素释放激素激动剂6个月。然后将患者转移到相反的药物治疗，直到前列腺特异性抗原进展（口服B期）。在整个研究过程中同样监测睾酮和二羟睾酮。在口服A期，沙利度胺组达到前列腺特异性抗原进展的中位时间为15个月，而安慰剂组为9.6个月（p = 0.21）。口服B期沙利度胺组达到前列腺特异性抗原进展的中位时间为17.1个月，而安慰剂组为6.6个月（p = 0.0002）。在口服A期和口服b期期间，沙利度胺组和安慰剂组在血清睾酮正常化的时间上没有差异。沙利度胺是耐受的，尽管有47%（124名患者中的58名）的患者出现了剂量减少。尽管沙利度胺对睾酮正常化没有影响，但在口服b期期间，对前列腺特异性抗原进展有明显影响。据我们所知，这是第一个证明沙利度胺使用间歇性激素治疗效果的研究。口服来那度胺治疗难治性转移性癌症：本研究的目的是确定来那度胺在晚期难治性实体肿瘤患者中的最大耐受剂量，并描述来那度胺的副作用和药代动力学特征。患者接受改良的Fibronacci剂量递增方案，每日口服来那度胺剂量。共纳入8种不同肿瘤类型的45例患者。给药剂量包括5、10和20毫克连续每日剂量，每28天（n = 15），后来修改为15、20、25、30、35和40毫克的间歇剂量，由于观察到的副作用，使用21天和7天的时间表。来那度胺在大剂量范围内呈线性药代动力学，平均半衰期为3.9小时。肾功能影响来那度胺清除率，导致轻度肾功能损害患者比功能正常患者减少50% （CL/F = 243 mL/min）。44例可评估患者中有12例病情稳定，其中9例患有前列腺癌。最常见的1级和2级毒性包括疲劳、恶心、瘙痒/皮疹、中性粒细胞减少和神经病变。3/4级事件主要为血液学。来那度胺的耐受性良好，可达35mg /d的间歇给药方案，剂量高于先前用于血液恶性肿瘤的适应症。

Following the publication of two landmark randomized trials, docetaxel chemotherapy is now the standard of care for men with metastatic CRPC. However, the benefit of this treatment is limited. Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biological agents. Several new docetaxel-based combinations are under evaluation and promising results have been found for the combination of docetaxel with angiogenesis inhibitors. We are attempting to develop novel agents that alter the biology of the cancer. In order to accomplish this goal, we have initiated a collaboration with a unique computational chemistry company to design compounds that abrogate key molecular targets in the development, progression and metastasis of cancer. These studies are just being initiated but could provide valuable new agents. Following previous experiments demonstrating increased efficacy of microtubule-active drugs when combined with ketoconazole in vitro, when tested in multiple prostate cancer cell lines, we initiated a Phase I trial of ketoconazole plus weekly docetaxel in patients with androgen independent prostate cancer (AIPC). The primary objective of this study is to determine the side effect profile and MTD. In recognition of possible drug-drug interations, starting doses of 5 mg/m2 and 1200 mg/d were used for docetaxel and ketoconazole, respectively. Significant hepatotoxicity was noted with a docetaxel dose of 10 mg/m2. The dosing regimen was modified to 600 mg/d of ketoconazole and 10 mg/m2 of docetaxel. A total of 30 patients have been treated with this combination to date and pharmacokinetic analyses are currently ongoing. A randomized Phase II trial of ketoconazole plus alendronate versus ketoconazole alone has been completed with 72 patients with progressive AIPC metastatic to bone. There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC. A Phase II study in AIPC has recently been completed with perifosine. Treatment with this agent was complicated by fatigue and gastrointestinal toxicity. No significant clinical activity against prostate cancer was observed. Perifosine does not merit further study in the setting of monotherapy in this population. Sorafenib for castration-resistant prostate cancer (CRPC): To determine if sorafenib is associated with an improved 4-month probability of progression-free survival, using radiographic and clinical criteria alone, we conducted a phase 2 trial in patients with metastatic CRPC. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival. The study was an open-label, phase II, two-stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28-day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks. Twenty-four patients were accrued in the second stage; the median (range) age was 66 (49-85) years, the on-study prostate-specific antigen level was 68.45 (5.8-995) ng/mL, the Gleason score 8 (6-9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft-tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15-48). At a median potential follow-up of 27.2 months, the median progression-free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand-foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue. Sorafenib has moderate activity as a second-line treatment for metastatic castration-resistant prostate cancer. Thalidomide versus placebo for androgen dependent prostate cancer treated with intermittent androgen ablation: We determined whether thalidomide can prolong progression-free survival in men with biochemically recurrent prostate cancer treated with limited androgen deprivation therapy. A total of 159 patients were enrolled in a double-blind randomized trial to determine if thalidomide can improve the efficacy of a gonadotropin-releasing hormone agonist in hormone responsive patients with an increasing prostate specific antigen after primary definitive therapy for prostate cancer. Patients were randomized to 6 months of gonadotropin-releasing hormone agonist followed by 200 mg per day oral thalidomide or placebo (oral phase A). At the time of prostate specific antigen progression gonadotropin-releasing hormone agonist was restarted for 6 additional months. Patients were then crossed over to the opposite drug and were treated until prostate specific antigen progression (oral phase B). Testosterone and dihydroxytestosterone were likewise monitored throughout the study. During oral phase A the median time to prostate specific antigen progression was 15 months for the thalidomide group compared to 9.6 months on placebo (p = 0.21). The median time to prostate specific antigen progression during oral phase B for the thalidomide group was 17.1 vs 6.6 months on placebo (p = 0.0002). No differences in time to serum testosterone normalization between the thalidomide and placebo arms were documented during oral phase A and oral phase B. Thalidomide was tolerable although dose reductions occurred in 47% (58 of 124) of patients. Despite thalidomide having no effect on testosterone normalization, there was a clear effect on prostate specific antigen progression during oral phase B. This is the first study to our knowledge to demonstrate the effects of thalidomide using intermittent hormonal therapy. Oral lenalidomide in patients with refractory metastatic cancer: The objectives of this study were to determine the maximum tolerated dose and to characterize the side effect profile and pharmacokinetics of lenalidomide in patients with advanced refractory solid tumors. Patients were treated on a modified Fibronacci dose escalation scheme with an oral daily dose of lenalidomide. A total of 45 patients with 8 different tumor types were accrued. Doses administered included 5, 10, and 20 mg continuous daily doses, every 28 days (n = 15), later modified to intermittent doses of 15, 20, 25, 30, 35, and 40 mg, with a 21 days-on and 7 days-off schedule, due to observed side effects. Lenalidomide exhibited a linear pharmacokinetics over a wide range of doses with the mean half-life of 3.9 hours. The renal function affected lenalidomide clearance, resulting in 50% reduction in patients with mild renal impairment compared with patients with normal function (CL/F = 243 mL/min). Stable disease was documented in 12 of 44 evaluable patients, of whom 9 patients had prostate cancer. Most frequent grade 1 and 2 toxicities included fatigue, nausea, pruritus/rash, neutropenia, and neuropathy. Grade 3/4 events were predominantly hematologic. Lenalidomide was well tolerated up to a 35-mg/d intermittent dosing schedule at doses higher than previously indicated for hematologic malignancies.