BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: PURPOSE:This study evaluated mechanistic differences of pralatrexate, methotrexate, and pemetrexed. METHODS:Inhibition of dihydrofolate reductase (DHFR) was quantified using recombinant human DHFR. Cellular uptake and folylpolyglutamate synthetase (FPGS) activity were determined using radiolabeled pralatrexate, methotrexate, and pemetrexed in NCI-H460 non-small cell lung cancer (NSCLC) cells. The tumor growth inhibition (TGI) was assessed using MV522 and NCI-H460 human NSCLC xenografts. RESULTS:Apparent K ( i ) values for DHFR inhibition were 45, 26, and >200 nM for pralatrexate, methotrexate, and pemetrexed, respectively. A significantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed. In vivo, pralatrexate showed superior anti-tumor activity in both NSCLC models, with more effective dose-dependent TGI in the more rapidly growing NCI-H460 xenografts. CONCLUSIONS:Pralatrexate demonstrated a distinct mechanistic and anti-tumor activity profile relative to methotrexate and pemetrexed. Pralatrexate exhibited enhanced cellular uptake and increased polyglutamylation, which correlated with increased TGI in NSCLC xenograft models.

背景与目标：

BACKGROUND & AIMS: :Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

背景与目标： : Pralatrexate抑制叶酸代谢，临床前研究表明它对多发性骨髓瘤细胞具有细胞毒性。这项1期研究调查了普拉瑞沙与硼替佐米联合治疗成人复发性或难治性多发性骨髓瘤的安全性和有效性。使用标准3 3设计。患者在每个4周周期的第1、8和15天接受10至30 mg/m(2) 的静脉注射普拉托雷酯和1·3 mg/m(2) 的静脉注射硼替佐米。11例患者入选并完成了两个周期的中位。最大耐受剂量为20 mg/m(2)。两名患者经历了粘膜炎的剂量限制性毒性。最常见的非血液学毒性是乏力 (55%) 和粘膜炎 (45%)。3例患者发生了3例严重不良事件: 皮疹、败血症和低血压。一名患者 (9%) 具有非常好的部分反应，1名患者 (9%) 具有部分反应，1名患者 (9%) 具有最小反应，两名患者 (18%) 具有进行性疾病。中位缓解持续时间为4个月，至下一次治疗的中位时间为3·4个月，中位进展时间为4个月。Pralatrexate联合硼替佐米通常是安全的，并且在复发或难治性多发性骨髓瘤中表现出适度的活性。临床医生.Gov标识符: nct01114282。

BACKGROUND & AIMS: :It has been nearly 8 years since pralatrexate became the first drug approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Like most drugs approved for a particular clinical indication, as much or more is learned once it enters mainstream use as in the years leading up to regulatory approval. Over the past several years, many diverse lines of research have shed new insight into both the agent, and the diseases it treats. In this review, we will bring the reader up to date on the many new aspects related to pralatrexate's pharmacology, activity across the panoply of T-cell lymphoproliferative malignancies, as well as some new and emerging guidelines that are likely to improve its safety profile. Finally, the review will close with the many new lines of evidence building a rationale for the combination of these novels: novel combination, and the vision for new platforms in PTCL care.

背景与目标： : 自普拉曲酯成为美国食品药品监督管理局批准的第一种用于治疗复发性或难治性外周T细胞淋巴瘤 (PTCL) 的药物以来，已有近8年的历史。像大多数被批准用于特定临床适应症的药物一样，一旦进入主流应用，就会学到更多或更多，就像在获得监管部门批准之前的几年一样。在过去的几年中，许多不同的研究领域对药物及其治疗的疾病都有了新的认识。在这篇综述中，我们将向读者介绍与普拉雷斯特的药理学，整个T细胞淋巴增生性恶性肿瘤的活动有关的许多新方面，以及一些可能改善其安全性的新指南。最后，审查将以许多新的证据为结束，这些小说的结合建立了基础: 小说的结合以及PTCL护理新平台的愿景。

BACKGROUND & AIMS: INTRODUCTION:Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of T-cell neoplasms. Most patients with PTCL have a poor outcome with conventional therapies and are not cured without stem-cell transplantation. Pralatrexate, a novel antifolate chemotherapeutic agent, was rationally designed to impede folate metabolism by inhibiting dihydrofolate reductase (DHFR) and to be more efficiently internalized into tumor cells. Pralatrexate is the first drug that is FDA approved for patients with relapsed and refractory PTCL. AREAS COVERED:Pralatrexate has been used as a single agent and in combination with other agents in clinical trials for non-Hodgkin's lymphoma and Hodgkin's disease as well as in solid tumors. This review will cover the development of pralatrexate, the pharmacokinetics of pralatrexate, preclinical findings with pralatrexate and clinical studies of pralatrexate in hematologic malignancies. EXPERT OPINION:Pralatrexate has significant activity in vitro, and in early Phase I/II trials, responses were noted in patients with aggressive T-cell lymphomas. The Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma trial demonstrated the activity of pralatrexate across a spectrum of heavily pretreated patients with different aggressive T-cell lymphoma subtypes, and studies in cutaneous T-cell lymphoma have shown efficacy at different doses and schedules. The most frequent adverse events in these trials were mucositis, reversible thrombocytopenia and fatigue.

背景与目标：

BACKGROUND & AIMS: :Pralatrexate is a folate analogue metabolic inhibitor manufactured by Allos Therapeutics, Inc., a wholly-owned subsidiary of Spectrum Pharmaceuticals, Inc. In both preclinical and clinical studies, pralatrexate demonstrated activity in lymphoma. Pralatrexate was US FDA approved for the treatment of relapsed/refractory peripheral T-cell lymphoma in 2009. Approval was based on data from the PROPEL trial that demonstrated an overall response rate of 29% in a heavily pretreated patient population. The dose and schedule of pralatrexate is 30-mg/m(2) weekly for 6 weeks, given in 7-week cycles. Folate and vitamin B12 supplementation are required to minimize toxicity. The most common toxicities are mucositis, thrombocytopenia, nausea and fatigue.

背景与目标： : Pralatrexate是一种叶酸类似物代谢抑制剂，由Spectrum Pharmaceuticals，Inc.的全资子公司Allos Therapeutics，Inc.生产。在临床前和临床研究中，普拉酯在淋巴瘤中均具有活性。Pralatrexate已被美国FDA批准用于治疗复发/难治性外周T细胞淋巴瘤2009年。批准是基于PROPEL试验的数据，该试验证明在经过大量预处理的患者人群中总体缓解率为29%。pralatrexate的剂量和时间表为每周30 mg/m(2)，持续6周，以7周为周期。需要补充叶酸和维生素B12以最大程度地减少毒性。最常见的毒性是粘膜炎，血小板减少症，恶心和乏力。

BACKGROUND & AIMS: BACKGROUND:Several previous clinical trials have shown that malignant pleural mesothelioma is responsive to antifolates. The dihydrofolate reductase inhibitor, pralatrexate, has a favorable toxicity profile, primarily limited to stomatitis, and has demonstrated activity in patients with non-small cell lung cancer. In mesothelioma cell lines and xenografts, pralatrexate demonstrated significant antitumor activity. METHODS:We conducted this phase II study to determine the response rate of malignant pleural mesothelioma to pralatrexate at a dose of 135 mg/m2 i.v. every 2 weeks. After a protocol amendment, patients were supplemented with vitamin B12 and folic acid at the time of starting therapy. RESULTS:A total of 16 assessable patients were enrolled. No complete or partial responses were observed. Two patients with epithelioid histology had minor responses. Three other patients remained on study with stable disease for 9, 9, and 48 months. The median time to progression was 3 months. The overall median survival time was 7 months (95% confidence interval: 3.2-16.2 months) and the one-year survival was 31% (95% confidence interval: 15%-65%). Three patients (19%) had grade 2 stomatitis, eight (50%) had grade 3, and one (6%) had grade 4. CONCLUSIONS:With this particular dose and schedule, pralatrexate as a single agent had no activity in malignant pleural mesothelioma.

背景与目标：

BACKGROUND & AIMS: INTRODUCTION:Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities. METHODS:Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response. RESULTS:Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2). CONCLUSIONS:Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.

背景与目标：

BACKGROUND & AIMS: :Here we report on the treatment of a 38-year-old woman with primary cutaneous γδT-cell lymphoma, which is a rare subset of cutaneous T-cell lymphoma. She presented with multiple subtle subcutaneous nodules, which were not clearly observed on computed tomography scans or after biopsy. However, F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) accurately detected small cutaneous lesions. She achieved a second complete remission, as demonstrated by F-FDG-PET performed after pralatrexate infusion.

背景与目标： : 在这里，我们报道了一名38岁女性原发性皮肤 γ δ T细胞淋巴瘤的治疗，这是皮肤T细胞淋巴瘤的罕见子集。她出现了多个细微的皮下结节，在计算机断层扫描或活检后均未清楚观察到。但是，F-氟脱氧葡萄糖正电子发射断层扫描 (f-fdg-pet) 准确地检测到了小的皮肤病变。如pralatrexate输注后进行的f-fdg-pet所示，她获得了第二次完全缓解。

BACKGROUND & AIMS: IMPORTANCE OF THE FIELD:Pralatrexate (PDX; 10-propargyl 10-deazaaminopterin), is an exciting new chemotherapeutic agent that is approved for the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). This is the only approved therapy for patients with PTCL. AREAS COVERED IN THIS REVIEW:This review describes the clinical development of PDX from its synthesis to its FDA approval. It details the biochemical basis of the differences between PDX and other antifolates that form the basis of the superiority of its activity. This is followed by a description of the preclinical data that led to early-phase clinical trials in lung cancer and lymphoma and, finally, the definitive trial that led to its approval in PTCL. The review also describes how PDX is being combined with other agents in both the preclinical and clinical arenas. WHAT THE READER WILL GAIN:These trials have been instrumental in defining a safe dose as well as the safety profile of the agent. FDA approval for the use of PDX in PTCL has been granted based on the results of the pivotal Phase II trial of this agent in relapsed and refractory PTCL patients. TAKE HOME MESSAGE:PDX is a unique antifolate that has been rationally designed to have a high affinity for the reduced folate receptor (RFC-1) and the enzyme folylpolyglutamy synthetase. It is active in T-cell lymphomas and non-small-cell lung cancer. It is now being studied in combination with other chemotherapeutic and targeted agents for the treatment of hematological malignancies.

背景与目标：

BACKGROUND & AIMS: INTRODUCTION:Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease. METHODS:In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) ≥1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more. RESULTS:A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%. CONCLUSIONS:Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.

背景与目标：

BACKGROUND & AIMS: :Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas with poor clinical outcomes. Pralatrexate showed efficacy and safety in recurrent or refractory PTCLs. The purpose or this study was to investigate the efficacy and safety of pralatrexate in relapsed or refractory PTCLs in real-world practice. This was an observational, multicenter, retrospective analysis. Between December 2012 and December 2016, a total of 38 patients with relapsed or refractory PTCLs were treated with pralatrexate at 10 tertiary hospitals in Korea. Patients received an intravenous infusion of pralatrexate at a dose of 30 mg/m2/week for 6 weeks on a 7-week schedule. Modified dosing and/or scheduling was allowed according to institutional protocols. Median patient age was 58 years (range, 29-80 years) and the most common subtype was peripheral T-cell lymphoma, not otherwise specified (n = 23, 60.5%). The median dosage of pralatrexate per administration was 25.6 mg/m2/wk (range, 15.0-33.0 mg/m2/wk). In intention-to-treat analysis, 3 patients (7.9%) showed a complete response and 5 patients (13.2%) showed a partial response, resulting in an overall response rate (ORR) of 21.1%. The median duration of response was 7.6 months (range, 1.6-24.3 months). The median progression-free survival (PFS) was 1.8 months (95% confidence interval [CI], 1.7-1.8 months) and the median overall survival was 7.7 months (95% CI, 4.4-9.0 months). The most common grade 3/4 adverse events were thrombocytopenia (n = 13, 34.2%), neutropenia (n = 7, 23.7%), and anemia (n = 7, 18.4%). Our study showed relatively lower ORR and shorter PFS in patients with recurrent or refractory PTCLs treated with pralatrexate in real-world practice. The toxicity profile was acceptable and manageable. We also observed significantly lower dose intensity of pralatrexate in real-world practice.

背景与目标： : 外周T细胞淋巴瘤 (PTCL) 是一组非霍奇金淋巴瘤，临床预后较差。Pralatrexate在复发性或难治性ptcl中显示出有效性和安全性。本研究的目的或本研究是在现实世界中研究普拉曲沙酯在复发或难治性ptcl中的疗效和安全性。这是一项观察性，多中心，回顾性分析。在2012年12月和2016年12月之间，共有38例复发或难治性ptcl患者在韩国的10家三级医院接受了pralatrexate治疗。患者在7周的时间表中接受30 mg/m2/周的pralatrexate的静脉输注，持续6周。根据机构协议，允许修改剂量和/或计划。中位患者年龄为58岁 (范围，29-80岁)，最常见的亚型是外周T细胞淋巴瘤，未明确说明 (n   =   23，60.5%)。Pratrexate每次给药的中位剂量为25.6  mg/m2/wk (范围为15.0-33.0  mg/m2/wk)。在意向治疗分析中，3例患者 (7.9%) 显示完全缓解，5例患者 (13.2%) 显示部分缓解，总缓解率 (ORR) 为21.1%。中位缓解持续时间为7.6个月 (范围，1.6-24.3个月)。中位无进展生存期 (PFS) 为1.8个月 (95% 置信区间 [CI]，1.7-1.8个月)，中位总生存期为7.7个月 (95% CI，4.4-9.0个月)。最常见的3/4级不良事件是血小板减少症 (n   =   13，34.2%) 、中性粒细胞减少症 (n   =   7，23.7%) 和贫血 (n   =   7，18.4%)。我们的研究表明，在现实世界中，使用普拉雷酯治疗的复发性或难治性ptcl患者的ORR相对较低，PFS较短。毒性特征是可接受且可控制的。我们还观察到在现实世界中pralatrexate的剂量强度明显降低。

BACKGROUND & AIMS: :Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survival, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.

背景与目标： : 使用常规CHOP (环磷酰胺，阿霉素，长春新碱，泼尼松) 化疗，外周T细胞淋巴瘤 (PTCL) 的结局不佳。抗叶酸普拉曲酯是第一种批准用于复发/难治性PTCL患者的药物，提供了将其纳入一线环境的理由。这项2期研究评估了一种新型的一线组合，在PTCL中环磷酰胺，依托泊苷，长春新碱和泼尼松 (CEOP) 与普拉曲酯 (ceop-p) 交替使用。达到完全或部分缓解 (CR/PR) 的患者在4个周期后有资格进行巩固干细胞移植 (SCT)。治疗了33例ii-iv期PTCL患者: 21例PTCL-未另外指定 (64%)，8例血管免疫母细胞性T细胞淋巴瘤 (24%) 和4例间变性大细胞淋巴瘤 (12%)。大多数 (61%) 患有IV期疾病，46% 是国际预后指数高/中或高风险。3-4级毒性包括贫血 (27%)，血小板减少症 (12%)，发热性中性粒细胞减少症 (18%)，粘膜炎 (18%)，败血症 (15%)，肌酐升高 (12%) 和肝转氨酶 (12%)。17名患者 (52%) 获得CR。2年无进展生存期和总生存期分别为39% (95% 置信区间21-57) 和60% (95% 置信区间39-76)。15例患者 (45% 例) (12例CR) 接受了SCT，中位随访时间为21·5个月，所有患者均保留在CR中。与使用CHOP的历史数据相比，ceop-p没有改善结局。在PTCL中定义最佳的一线治疗仍然是一个挑战，也是一个未得到满足的需求。

BACKGROUND & AIMS: PURPOSE:The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans. METHODS:The starting dose was pralatrexate 40 mg/m(2) intravenously and probenecid 70 mg/m(2) intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1. RESULTS:Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m(2) and probenecid 233 mg/m(2). Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen. CONCLUSION:For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m(2) and probenecid 140 mg/m(2). Vitamin B(12) and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study.

背景与目标：

BACKGROUND & AIMS: INTRODUCTION:Peripheral T cell lymphomas (PTCL) are a heterogenous group of lymphoproliferative disorders which are generally not curable with conventional chemotherapy and associated with inferior outcomes. Pralatrexate is a novel folate analog, the first FDA approved drug) for the treatment of relapsed/refractory (R/R) PTCL. AREAS COVERED:This paper provides a comprehensive review of PubMed literature describing the use of pralatrexate in R/R peripheral T-cell lymphoma. Pharmacokinetics and mechanism of action of pralatrexate are discussed as well as its clinical efficacy and safety in comparison to other agents available in R/R PTCL. EXPERT OPINION:Pralatrexate is an active agent in relapsed/refractory PTCL with lower response rates seen in patients with angioimmunoblastic T cell lymphomas. Mucositis is the most frequently observed adverse event and this can be mitigated by the use of leucovorin along with cyanocobalamin and folic acid.

背景与目标：