Drug Development for Prostate Cancer and other Metastatic Processes

我们对CRPC进展生物学的理解导致发现了更有效的靶向方法，这些方法涉及雄激素- ar系统的调节。我们对CYP17A1抑制剂和雄激素受体拮抗剂的临床前和临床开发感兴趣，致力于开发新型药物，并表征已上市药物的临床药理学和/或治疗反应。我们与Ravi Madan博士（GMB， CCR， NCI）合作，最近完成了一项开放标签II期临床试验，评估了七维龙对先前接受过enzalutamide治疗的mCRPC患者的耐受性和疗效。Seviteronel是一种选择性细胞色素P450c17a (CYP17) 17,20-裂解酶（lyase）抑制剂和雄激素受体拮抗剂，在体外和体内对前列腺癌细胞具有活性。既往在接受恩杂鲁胺治疗时病情进展的mCRPC患者根据既往多西紫杉醇暴露情况分为2组。在不使用常规口服类固醇的情况下，每天两次剂量滴定（450毫克）或每天一次剂量滴定（600或750毫克）。主要目的是确定在七维龙治疗12周后显著的前列腺特异性抗原应答率（即下降50%）。17例患者入组，中位（范围）年龄为71岁（60-92岁），其中8例患者先前接受过多西他赛。患者接受中位数为2个周期的治疗，大多数患者因与研究药物相关的毒性而停止治疗。最常见的不良事件包括注意力障碍、疲劳、震颤和恶心。尽管剂量有所变化，但由于毒性很大，该研究过早结束。17例患者中有1例（6%）的前列腺特异性抗原显著下降。在先前接受过恩杂鲁胺治疗的mCRPC患者中，Seviteronel的耐受性一般不佳，也与显著的临床反应相关。在该患者群体中进一步研究单药七韦列酮是不合理的；然而，在雄激素受体阳性肿瘤患者中，关于七维龙与低剂量地塞米松联合的研究正在进行中。我们还对晚期/转移性CRPC或乳腺癌患者进行了七维龙的人群药代动力学分析。本研究通过4项临床研究，对243例晚期乳腺癌或前列腺癌患者采用非室室和群体方法，描述了七维龙（50- 750mg， QD或BID）的PK。检查首次给药和稳态PK，以及包括饮食状态、性别和伴随使用地塞米松在内的协变量。在考虑随机效应之间的协方差时，七iteronel的PK可以通过传输吸收和双相一阶消除来表征。膳食状态对临床相关参数没有显著影响。性别和体重都是清除率的重要协变量，解释了该参数的37%的个体间变异性。种族或皮质类固醇（地塞米松或泼尼松）的存在没有显著影响。在50- 750mg的剂量范围内，对于晚期CRPC男性或乳腺癌男性和女性患者，无论是BID还是QD， Seviteronel均显示出线性PK。该人群PK模型很好地描述了口服给药后七维列酮的处置，并可用于准确模拟体重和性别影响清除率的未来研究，但没有达到临床意义的程度，需要改变当前的给药方案。我们对了解前列腺癌治疗方案的耐药机制很感兴趣。肿瘤内缺氧也与CRPC进展和治疗抵抗有关。缺氧肿瘤细胞中缺氧诱导因子-1 α (HIF-1a)的上调通过增加血管生成和转移提供了对当前激素治疗和化疗获得性耐药的机制。考虑到AR和HIF-1a都是这些过程的关键调节因子，双重靶向两个信号轴代表了一种有吸引力的治疗方法。Enzalutamide是一种有效的第二代雄激素受体（AR）拮抗剂，在CRPC中具有活性。虽然恩杂鲁胺最初是有效的，但随着耐药性的出现，疾病不可避免地会进展。恩杂鲁胺对mCRPC患者在疾病进展后的有效治疗目前是一个未满足的临床需求。我们实验室之前的研究表明，在体外同时抑制HIF-1a和AR通路会导致AR和hif依赖性表达和前列腺癌细胞生长的协同抑制，这可能是克服恩杂鲁胺耐药和增强抗AR治疗的一种机制。NLG207（原CRLX101）是一种纳米颗粒药物偶联物，由20(S)-喜树碱（一种有效的高选择性拓扑异构酶I抑制剂）和HIF1a抑制剂组成。在临床前前列腺癌模型中评估NLG207与恩杂鲁胺联合治疗对恩杂鲁胺的耐药性。采用22Rv1皮下移植瘤模型和去势VCaP皮下移植瘤模型，在体内评价NLG207和恩杂鲁胺对肿瘤平均体积和治疗3周后肿瘤再生长的影响。在22Rv1皮下异种移植模型中，与对照相比，NLG207联合enzalutamide治疗3周后，平均肿瘤体积减少93% (p0.05)，中位肿瘤生长速度减少54% （p0.0001）。NLG207的加入也增强了单独恩杂鲁胺在去势皮下VCaP异种移植模型中的疗效，使肿瘤生长的中位率降低了51% （p=0.0001）。体外对细胞增殖和基因表达的评估进一步证明了AR-HIF-1a串音抑制的抗肿瘤活性。NLG207联合恩杂鲁胺治疗对恩杂鲁胺耐药的临床前前列腺癌模型有效。与Madan博士（NCI）合作，我们目前正在招募患者进行单组试点研究，以评估在先前接受过enzalutamide治疗（NCT03531827）的进行性mCRPC患者中，CRLX101联合enzalutamide的安全性和活性。此外，我们在成人晚期实体瘤患者中进行了NLG207的群体药代动力学分析，以表征NLG207的复杂PK，并使用半机械群体PK （popPK）模型更好地描述纳米颗粒中CPT的释放。从27名参加两项II期临床试验（NCT02769962和NCT03531827）的患者中，在第1或第6周期给药NLG207后48小时进行密集抽样；在给药后360小时采集样本。从每个样品中定量结合和游离CPT浓度，得到477个观测值，利用非线性混合效应建模建立popPK模型。NLG207的PK通过结合两个线性双室模型来表征，每个模型都具有一阶动力学来描述结合和游离CPT。基于体重的异速缩放为所有PK参数提供了最佳的体型描述符。半机制popk模型证实了结合CPT的纳米颗粒行为，并对NLG207释放CPT的机理进行了表征。目前的分析为未来的研究提供了坚实的基础，作为正在进行的NLG207临床试验的潜在预测工具。

Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of CYP17A1 inhibitors and androgen receptor antagonists, with efforts on developing novel agents and characterizing the clinical pharmacology and/or treatment response of marketed agents. In collaboration with Dr. Ravi Madan (GMB, CCR, NCI), we recently completed an open-label phase II clinical trial evaluating the tolerability and efficacy of seviteronel in patients with mCRPC previously treated with enzalutamide. Seviteronel is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) inhibitor and androgen receptor antagonist with activity against prostate cancer cells in vitro and in vivo. Patients with mCRPC whose disease previously progressed while receiving enzalutamide therapy were divided into 2 cohorts on the basis of prior exposure to docetaxel. Seviteronel was administered without routine oral steroids either twice daily with dose titration (450 mg) or once daily without dose titration (600 or 750 mg). The primary objective was to determine the rate of significant prostate-specific antigen response (ie, decline of 50%) after 12 weeks of seviteronel therapy. Seventeen patients, with a median (range) age of 71 (60-92) years, were enrolled, with 8 patients having received prior docetaxel. Patients received a median of 2 cycles of treatment, with most patients discontinuing treatment because of toxicity related to the study drug. The most common adverse events included concentration impairment, fatigue, tremor, and nausea. Despite changes in dosing, the study was closed prematurely because of the high magnitude of toxicity. One (6%) of 17 patients experienced a significant decline in prostate-specific antigen. Seviteronel was not generally well tolerated nor associated with significant clinical responses in patients with mCRPC who had previously received enzalutamide. Further investigation of single-agent seviteronel in this patient population is not warranted; however, studies investigating seviteronel with low-dose dexamethasone are ongoing in patients with androgen receptor-positive tumors. We also conducted a population pharmacokinetic analysis of seviteronel in patients with advanced/metastatic CRPC or breast cancer. This study describes the PK of seviteronel (50-750 mg, QD or BID) using noncompartmental and population approaches from 243 patients with advanced breast or prostate cancer pooled across 4 clinical studies. First dose and steady-state PK were examined, as well as covariates including prandial status, sex and concomitant dexamethasone. Seviteronel PK can be characterized by transit absorption and a bi-phasic first-order elimination while accounting for covariance between random effects. Prandial status did not significantly affect any parameters to a clinically-relevant extent. Both sex and body weight were significant covariates on clearance, explaining 37% of the interindividual variability on that parameter. There were no significant effects from the race or the presence of a corticosteroid (either dexamethasone or prednisone). Seviteronel demonstrates linear PK over the dose range of 50-750 mg given either BID or QD in men with advanced CRPC or men and women with breast cancer. The disposition of seviteronel following oral administration is well described by this population PK model and can be used for accurate simulations for future studies with body weight and sex affecting clearance, but not to a clinically-meaningful degree requiring a change in the current dosing scheme. We are interested in understanding the mechanisms of resistance of prostate cancer regimens. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Upregulation of hypoxia inducible factor-1alpha (HIF-1a) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies by increasing angiogenesis and metastasis. Given that both AR and HIF-1a are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in CRPC. Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Effective treatments for patients with mCRPC following disease progression on enzalutamide is currently an unmet clinical need. Our laboratory has previously shown that simultaneous inhibition of HIF-1a and AR pathways in vitro resulted in synergistic inhibition of AR-and HIF-dependent expression and prostate cancer cell growth, suggesting a possible mechanism for overcoming enzalutamide resistance and potentiating anti-AR therapy. NLG207 (formerly CRLX101) is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent and highly selective topoisomerase I inhibitor) and a HIF1a inhibitor. Combination treatment with NLG207 and enzalutamide was evaluated in preclinical prostate cancer models of enzalutamide resistance. The effect of NLG207 and enzalutamide on average tumor volume and tumor re-growth after 3 weeks of treatment were evaluated in vivo using the subcutaneous 22Rv1 xenograft and castrated subcutaneous VCaP xenograft models. NLG207 in combination with enzalutamide reduced average tumor volume by 93% after 3 weeks of treatment (p0.05) and reduced the median rate of tumor growth by 54% (p0.0001) in comparison to vehicle control in the subcutaneous 22Rv1 xenograft model. The addition of NLG207 also enhanced the efficacy of enzalutamide alone in the castrated subcutaneous VCaP xenograft model, decreasing the median rate of tumor growth by 51% (p=0.0001). In vitro assessments of cell proliferation and gene expression further demonstrated anti-tumor activity via AR-HIF-1a crosstalk inhibition. Combination treatment with NLG207 and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. In collaboration with Dr. Madan (NCI), we are currently enrolling patients on a single arm pilot study to evaluate the safety and activity of combining CRLX101 with enzalutamide in patients with progressive mCRPC following prior enzalutamide treatment (NCT03531827). Moreover, we conducted a population pharmacokinetic analysis of NLG207 in adults with advanced solid tumors to characterize the complex PK of NLG207 and better describe CPT release from nanoparticles using a semi-mechanistic population PK (popPK) model. From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 hours post-administration of NLG207 during cycle one or six of treatment; samples were also collected at 360 hours post-dose. Bound and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modelling. The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe bound and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The semi-mechanistic popPK model confirmed nanoparticle behavior of bound CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.