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.

在两项具有里程碑意义的随机试验发布后，多西他赛化疗现在是转移性CRPC男性的护理标准。但是，这种治疗的好处是有限的。现在，试验专注于通过将其与新型生物学剂相结合来提高多西他赛的功效。在评估中，几种新的基于多西他赛的组合正在评估中，并且发现多西他赛与血管生成抑制剂的组合发现了令人鼓舞的结果。我们正在尝试开发改变癌症生物学的新型药物。为了实现这一目标，我们已经与一家独特的计算化学公司合作，设计了消除癌症发展，进展和转移中关键分子靶标的化合物。这些研究只是开始启动，但可以提供有价值的新代理商。在先前的实验表明与酮康唑在体外结合使用微管激活药物的功效增加后，当在多个前列腺癌细胞系中进行测试时，我们启动了酮康唑和每周Docetaxel在雄激素独立前列腺癌（AIPC）患者中进行的I期试验。这项研究的主要目的是确定副作用曲线和MTD。为了识别可能的药物 - 药物中间，分别将5 mg/m2和1200 mg/d的起始剂量用于多西他赛和酮康唑。多西他赛剂量为10 mg/m2。将剂量方案修改为600 mg/d的酮康唑和10 mg/m2多西他赛。迄今为止，总共有30名患者接受了此组合的治疗，目前正在进行药代动力学分析。酮康唑和阿甘膦酸盐与酮康唑的一项随机II期试验已经完成了72例进行性AIPC转移性骨骼的患者。 AIPC患者的反应率，无进展生存期和KT/H加上Al治疗之间的反应率，无进展生存期或总体存活情况没有统计学上的显着差异。与单独使用KT/H的治疗相比，在KT/H中添加Al可能会增加可接受的安全性。但是，AL的添加对AIPC患者没有生存益处。 perifosine最近在AIPC进行了II期研究。该药物的治疗因疲劳和胃肠道毒性而复杂。未观察到针对前列腺癌的明显临床活性。 perifosine在该人群的单一疗法中不值得进一步的研究。索拉非尼用于cast割耐药的前列腺癌（CRPC）：确定索拉非尼是否仅使用放射线学和临床标准就可以改善无进展生存的4个月概率，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，毒性分析和整体生存。这项研究是开放标签的II期，两阶段的设计，重点是第二阶段的结果，因为完成第一阶段后，对进程的标准进行了修改。索拉非尼在28天的周期中以400毫克口服的剂量服用400毫克。每4周进行一次临床和实验室评估，每8周进行一次射线照相扫描。第二阶段累计二十四名患者；中位（范围）年龄为66（49-85）年，研究中的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）和东部合作肿瘤学组状态1（17名患者中）。在24例患者中，有21例先前对多西他赛进行化学疗法。所有患者都有骨转移（在11中）或软组织疾病（13）。一名患者有部分反应。 10例患者患有稳定的疾病（中位持续时间18周，范围15-48）。在中位潜在的随访27.2个月时，无进展的中位生存期为3.7个月，中位总生存期为18.0个月。对于46例患者的整个试验，中位生存期为18.3个月。最常见的毒性包括手脚皮肤反应（九名患者2级，三级三分之一），皮疹，肝功能检查异常和疲劳。索拉非尼具有中等活性作为二线治疗转移性cast割前列腺癌。用间歇性雄激素消融治疗的依赖雄激素依赖的前列腺癌的沙利度胺与安慰剂：我们确定丘里替胺是否可以延长患有有限雄激素剥夺治疗的生物化学复发性前列腺癌的男性中的无进展生存期。一项双盲随机试验中，共有159例患者被招募，以确定沙利度胺是否可以提高促性腺激素释放激素激素激素激素在原发性确定性治疗后对前列腺癌后前列腺特异性抗原增加的激素反应患者的疗效。患者被随机分配到促性腺激素释放激素激动剂的6个月，然后每天口服沙利度胺或安慰剂（口腔A期）200 mg。在前列腺特异性抗原进展时，促性腺激素释放激素激动剂又重新启动了6个月。然后将患者越过相对的药物，并接受治疗直至前列腺特异性抗原进展（口服B）。 在整个研究过程中，同样对睾丸激素和二羟基植物酮也受到监测。在A期A期间，沙利度胺组的前列腺特异性抗原进展的中位时间为15个月，而安慰剂为9.6个月（p = 0.21）。沙利度胺组在口服B期间前列腺特异性抗原进展的中值时间为17.1，安慰剂对6.6个月（p = 0.0002）。在口腔A期和口腔相处，沙利度胺和安慰剂组之间血清睾丸激素正常化的时间没有差异。沙利度胺是可以忍受的，尽管在124例患者中有47％（58）中降低了剂量。 尽管沙利度胺对睾丸激素的归一化没有影响，但在口腔相中，对前列腺特异性抗原进展有明显的影响。这是我们所知的首次研究，是使用间歇性的激素治疗来证明沙利度胺的影响。难治性转移性癌症患者的口服列纳替米：这项研究的目的是确定最大耐受剂量，并表征晚期耐火固体瘤患者的副作用概况和副作用。用改性的Fibronacci剂量升级方案对患者进行治疗，并用每日的Lenalidomide治疗。总共有45例患有8种不同肿瘤类型的患者。给予的剂量包括5、10和20 mg连续的每日剂量，每28天（n = 15），后来修改为15、20、25、30、35和40 mg的15、20、25、30、35和40 mg，由于观察到的副作用，其时间为21天和7天。 Lenalidomide在各种剂量的平均半衰期为3.9小时的范围内表现出线性药代动力学。与正常功能的患者相比，肾脏功能影响了多纳维胺的清除，导致轻度肾功能障碍患者降低50％（CL/F = 243 mL/min）。 44例可评估患者中有12例记录了稳定的疾病，其中9例患者患有前列腺癌。 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。 3/4级事件主要是血液学。 Lenalidomide的耐受性良好，达到35毫克/d的间歇性剂量时间表，其剂量比先前所指出的血液系统恶性肿瘤的剂量高。