Development of Drugs That Target Prostate Cancer

开发针对前列腺癌的药物

• 批准号: 7965416
• 负责人: William Douglas Figg
• 金额: $ 29.74万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965416
• 关键词: Ablation; Adverse effects; Affect; Age; Agonist; Alendronate; Androgens; Angiogenesis Inhibitors; Antineoplastic Agents; BAY 54-9085; Biological Products; Cancer Biology; Castration; Clinical; Collaborations; Development; Disease; Disseminated Malignant Neoplasm; Dose; Double-Blind Method; Drug Delivery Systems; Drug Kinetics; Eastern Cooperative Oncology Group; Enrollment; Evaluable Disease; Evaluation; Event; Exanthema; Exhibits; Failure; Fatigue; Genetic Crossing Over; Gleason Grade for Prostate Cancer; Goals; Gonadotropin Hormone Releasing Hormone; Half-Life; Hand; Hematologic Neoplasms; Hepatotoxicity; Hormone Responsive; Hour; Impairment; In Vitro; Ketoconazole; Kidney; Knowledge; Laboratories; Liver Function Tests; Malignant neoplasm of prostate; Maximum Tolerated Dose; Metastatic Neoplasm to the Bone; Metastatic to; Microtubules; Modeling; Moderate Exercise; Molecular Target; Monitor; Nausea; Neoplasm Metastasis; Neuropathy; Neutropenia; New Agents; Oral; PC3 cell line; Patients; Perifosine; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebos; Population; Probability; Prognostic Marker; Progression-Free Survivals; Prostate Cancer therapy; Prostate-Specific Antigen; Pruritus; Publications; Randomized; Randomized Controlled Clinical Trials; Reaction; Recurrence; Refractory; Renal function; Resistance; Safety; Scanning; Schedule; Scheme; Serum; Skin; Soft Tissue Disorder; Solid Neoplasm; Stable Disease; Staging; Testing; Testosterone; Thalidomide; Time; Toxic effect; Treatment Protocols; Treatment outcome; Upper arm; androgen independent prostate cancer; base; bone; chemotherapy; computational chemistry; deprivation; design; docetaxel; follow-up; foot; gastrointestinal; hormone therapy; improved; lenalidomide; men; metastatic process; novel; open label; partial response; research study; response; standard of care; tumor

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.

继两项具有里程碑意义的随机试验发表后，多西紫杉醇化疗现已成为男性转移性 CRPC 的治疗标准。然而，这种治疗的好处是有限的。目前试验的重点是通过将多西紫杉醇与新型生物制剂相结合来提高其疗效。几种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发现有希望的结果。我们正在尝试开发改变癌症生物学的新药物。为了实现这一目标，我们启动了与一家独特的计算化学公司的合作，设计能够消除癌症发生、进展和转移中关键分子靶标的化合物。这些研究刚刚开始，但可以提供有价值的新药物。先前的实验证明微管活性药物在体外与酮康唑联合使用可提高疗效，并在多种前列腺癌细胞系中进行测试，随后我们在雄激素非依赖性前列腺癌 (AIPC) 患者中启动了酮康唑加每周多西紫杉醇的 I 期试验。本研究的主要目的是确定副作用概况和 MTD。考虑到可能的药物相互作用，多西他赛和酮康唑的起始剂量分别为 5 mg/m2 和 1200 mg/d。 10 mg/m2 剂量的多西紫杉醇具有显着的肝毒性。给药方案修改为酮康唑 600 mg/d 和多西紫杉醇 10 mg/m2。迄今为止，共有 30 名患者接受了该组合的治疗，目前正在进行药代动力学分析。一项酮康唑加阿仑膦酸钠与单用酮康唑的随机 II 期试验已经完成，受试者为 72 名患有进行性 AIPC 骨转移的患者。 AIPC 患者中单独 KT/H 治疗和 KT/H 加 AL 治疗之间的缓解率、无进展生存期或总生存期没有统计学上的显着差异。与单独使用 KT/H 治疗相比，在 KT/H 中添加 AL 可能会增加缓解持续时间，且安全性可接受。然而，添加 AL 不会为 AIPC 患者带来生存获益。 AIPC 的 II 期研究最近已经完成了哌立福辛。使用这种药物的治疗因疲劳和胃肠道毒性而变得复杂。没有观察到显着的针对前列腺癌的临床活性。哌立福辛不值得在该人群中进行单一疗法的进一步研究。索拉非尼治疗去势抵抗性前列腺癌 (CRPC)：为了确定索拉非尼是否与改善 4 个月无进展生存概率相关，仅使用放射学和临床标准，我们在转移性 CRPC 患者中进行了一项 2 期试验。次要终点包括药代动力学、毒性分析和总生存期。该研究是开放标签、第二阶段、两阶段设计，重点关注第二阶段的结果，因为进展标准在完成第一阶段后进行了修改。索拉非尼的剂量为 400 mg，每天口服两次，周期为 28 天。每 4 周进行一次临床和实验室评估，每 8 周进行一次放射线扫描。第二阶段共招募了 24 名患者；中位（范围）年龄为 66 (49-85) 岁，研究中前列腺特异性抗原水平为 68.45 (5.8-995) ng/mL，格里森评分 8 (6-9)，东部肿瘤合作组状态1（17 名患者）。在 24 名患者中，21 名之前接受过多西紫杉醇化疗。所有患者均出现骨转移，有的是单独发生（11 例），有的是伴有软组织疾病（13 例）。一名患者出现部分反应； 10 名患者病情稳定（中位病程 18 周，范围 15-48）。中位潜在随访时间为 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 46 名患者参与的整个试验中，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 名患者为 2 级，3 名患者为 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。沙利度胺与安慰剂治疗间歇性雄激素消融治疗的雄激素依赖性前列腺癌：我们确定了沙利度胺是否可以延长接受有限雄激素剥夺治疗的生化复发性前列腺癌男性的无进展生存期。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初步确定治疗后前列腺特异性抗原增加的激素反应性患者的疗效。患者被随机分配接受 6 个月的促性腺激素释放激素激动剂治疗，随后每天口服 200 毫克沙利度胺或安慰剂（口服 A 期）。当前列腺特异性抗原进展时，促性腺激素释放激素激动剂重新开始使用 6 个月。然后，患者被换用相反的药物并接受治疗，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基睾酮。在口服 A 期期间，沙利度胺组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）。沙利度胺组口服 B 期期间前列腺特异性抗原进展的中位时间为 17.1 个月，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之间的血清睾酮正常化时间没有差异。沙利度胺是可耐受的，尽管 47%（124 名患者中的 58 名）发生了剂量减少。 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，这是第一项证明沙利度胺使用间歇性激素治疗的效果的研究。难治性转移性癌症患者口服来那度胺：本研究的目的是确定晚期难治性实体瘤患者中来那度胺的最大耐受剂量并表征来那度胺的副作用特征和药代动力学。患者接受改良的 Fibronacci 剂量递增方案治疗，每日口服剂量的来那度胺。总共有 45 名患者患有 8 种不同的肿瘤类型。给药剂量包括 5、10 和 20 mg 连续每日剂量，每 28 天一次（n = 15），后来修改为间歇剂量 15、20、25、30、35 和 40 mg，连续 21 天和由于观察到副作用，请假 7 天。来那度胺在大剂量范围内表现出线性药代动力学，平均半衰期为 3.9 小时。肾功能影响来那度胺的清除率，导致轻度肾功能不全患者的清除率比功能正常的患者减少50%（CL/F = 243 mL/min）。 44 名可评估患者中，有 12 名患者病情稳定，其中 9 名患者患有前列腺癌。 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 级事件主要是血液学事件。来那度胺的耐受性良好，高达 35 mg/d 的间歇给药方案，其剂量高于之前用于血液恶性肿瘤的剂量。