Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors

Purpose MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. Methods Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. Results Five dose levels of MAC-321 ranging from 25 to 75 mg/m² were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m²). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m²; one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m² had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1–2 fatigue and grades 1–2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C _max value of less than 1 h. Mean C _max and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20–228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). Conclusions MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m². The major DLT was neutropenic fever. Four subjects had disease stabilization.     

A phase I trial of docetaxel based induction and concomitant chemotherapy in patients with locally advanced head and neck cancer

The purpose of this study was to determine the maximum tolerated dose (MTD) of docetaxel based induction and concomitant chemoradiotherapy (CRT) after using the FHX platform (5 = 5-FU, H = hydroxyurea, X = Radiation). Patients with Stage III/IV locally advanced HNSCC were enrolled. Induction chemotherapy (carboplatin/docetaxel) was followed by 5 cycles of concomitant docetaxel based CRT. No DLTs were observed in dose levels 1/2 for induction and CRT. Dose level 2 was expanded. The overall survival CR rate after CRT was 79 percent. Median overall (OS) has not been reached and 2-year OS is 80.7 percent. The recommended Phase II dose of docetaxel with FHX CRT is 25 mg/m² and 35 mg/m² in combination with carboplatin induction (AUC = 6).     

Possible involvement of CCT5, RGS3, and YKT6 genes up-regulated in p53-mutated tumors in resistance to docetaxel in human breast cancers

Background Present study was aimed to investigate the relationship of p53 mutation status with response to docetaxel in breast cancers. In addition, attempts were made to identify the genes differentially expressed between p53-wild and p53-mutated breast tumors and to study their relationship with response to docetaxel. Methods Mutational analysis of p53 was done in 50 breast tumor samples obtained from primary breast cancer patients (n = 33) and locally recurrent breast cancer patients (n = 17) before docetaxel therapy. Response to docetaxel was evaluated clinically. Gene expression profiling (n = 2,412) was conducted by adapter-tagged competitive-PCR in 186 tumor samples, which were also analyzed in their p53 mutational status in order to identify the differentially expressed genes according to p53 mutation status and their relationship with response to docetaxel. Results Response rate of p53-mutated tumors (44%) was lower than that of p53-wild tumors (62%) though there was no statistical significance (P = 0.23). Of 2412 genes, mRNA expression of 13 genes was significantly different between p53-wild and p53-mutated tumors. Of these 13 genes, mRNA expression of CCT5, RGS3,␣and YKT6 was significantly up-regulated in p53-mutated tumors and associated with a low response rate to docetaxel. Treatment of MCF-7 cells with siRNA specific for CCT5, RGS3, or YKT6 resulted in a significant enhancement of docetaxel-induced apoptosis. Conclusions CCT5, RGS3, and YKT6 mRNA expressions, which are up-regulated in p53-mutated breast tumors, might be implicated in resistance to docetaxel and clinically useful in identifying the subset of breast cancer patients who may or may not benefit from docetaxel treatment.     

TEC及TE方案在乳腺癌新辅助化疗中的近期疗效及不良反应的对比分析

目的对比分析以紫杉醇类及蒽环类为基础加/不加环磷酰胺（TEC/TE）两种化疗方案在乳腺癌新辅助化疗中的疗效及不良反应。方法回顾性分析2012年1月至2014年4月本院收治的共139例Ⅱ~Ⅲ期浸润性导管癌患者的临床病理资料。所有患者均接受4个周期的新辅助化疗,其中TEC方案（多西他赛75 mg/m2＋表柔比星60 mg/m2＋环磷酰胺500 mg/m2）共68例,TE方案（多西他赛75 mg/m2＋表柔比星60 mg/m2）共71例。以RECIST标准判断临床疗效,完全缓解（complete response,CR）＋部分缓解（partial response,PR）为临床有效,以Miller Payne标准判断病理疗效,Ⅲ级＋Ⅴ级＋Ⅳ级为病理学有效,同时观察恶心、呕吐等不良反应。等级资料的比较采用非参数检验,计数资料采用χ2检验。结果 TEC组的p CR率、CR率分别为13.85%（9/68）和10.29%（7/68）,TE组为11.27%（8/71）和5.63%（4/71）,但差异无统计学意义（Z=-1.804、-1.336;P=0.071、0.181）。TEC组的病理有效率为78.46%（51/65,3例缺失病理数据）,显著高于TE组的61.97%（44/71）（χ2=4.382,P=0.036）,但两组的临床有效率差异无统计学意义[72.06%（49/68）比61.97%（44/71）,χ2=1.596,P=0.206]。TEC组及TE组的保留乳房率分别为5.88%（4/68）、8.45%（6/71）,差异均无统计学意义（χ2=0.066,P=0.797）。两组的常见不良反应为恶心呕吐、粒细胞减少症及心脏毒性,差异均无统计学意义（Z=-1.670、-0.667、-1.326;P=0.095、0.505、0.185）。结论与TE方案比较,患者接受TEC方案新辅助化疗更易获得病理学缓解,且不增加不良反应。TEC方案在新辅助化疗中有一定的应用前景。     

多西他赛单药与多西他赛联合铂类方案二线治疗晚期非小细胞肺癌的比较

目的 比较晚期非小细胞肺癌(NSCLC)患者二线治疗中多西他赛单药与多西他赛联合铂类方案的疗效及毒副反应,为NSCLC的二线规范治疗提供依据.方法 回顾性分析2004年1月至2008年5月在上海交通大学附属胸科医院接受二线化疗的152例晚期NSCLC患者的临床资料.40例接受多西他赛单药治疗(单药组),其中Ⅲb期16例,Ⅳ期24例;治疗前体力状况(PS)评分0～1分32例,2分8例.112例接受多西他赛联合铂类治疗(联合组),其中Ⅲb期29例,Ⅳ期83例;治疗前PS评分0～1分98例,2分14例.主要研究终点为总生存期(OS),次要研究终点为疾病控制率(DCR)、无疾病进展时间(PFS)、1年生存率及药物毒副反应.应用Kaplan-Meire方法进行生存分析,并进行各影响因素与预后关系的单因素及多因素分析.结果 单药组中位PFS(3.0个月)短于联合组(4.2个月,P=0.048),中位OS(17.0个月)、DCR(61.1%)和1年生存率(84.6%)与联合组(18.8个月、69.1%、86.9%)比较,差异均无统计学意义(均P0.05).单药组Ⅲ～Ⅳ度白细胞减少和胃肠道反应发生率分别为32.5%和0,均明显低于联合组(56.2%,4.5%,均P=0.000).预后因素分析显示既往接受手术[危险比(HR)=0.428,95%可信区间(CI)为0.261～0.701]、治疗前PS评分(HR=1.919,95% CI为0.999～3.685)、肿瘤分期(HR=2.297,95% CI为1.427～3.696)以及二线治疗获益(HR=0.318,95% CI为0.177～0.571)是NSCLC的独立预后因素.结论 多西他赛联合铂类方案二线治疗与多西他赛单药方案相比有助于延长一般情况较好的晚期NSCLC患者的无疾病进展时间,但未显著增加患者的总生存期,并可给患者带来更大的血液学及胃肠道毒性.     

Cost-effectiveness of trastuzumab biosimilar combination therapy and drug wastage as first-line treatment for HER2-positive metastatic breast cancer

BackgroundThe rising cost of cancer drug therapy threatens the long-term sustainability of Taiwan National Health Insurance. Cost savings can be achieved through various strategies, e.g., using smaller vial sizes, sharing vials, weight-based dosing, or switching to biosimilars. Here we aimed to examine the cost-effectiveness of a trastuzumab biosimilar combined with docetaxel (TDbiol) for treatment-naïve HER2⁺ metastatic breast cancer (MBC), and the financial impact of drug wastage.MethodsA Markov model with three health states was developed to assess the cost-effectiveness of trastuzumab biosimilars plus docetaxel over a 40-month time horizon in patients with HER2⁺ MBC. Based on the literature and our expert opinion, we assumed similar efficacy between the trastuzumab biosimilar and its reference product. The primary clinical input for the biosimilar was the same as for the reference product in the Catastrophic Patient Database (HV). Health state utilities were derived from the literature, and direct medical costs were obtained from the National Health Insurance Administration (NHIA).ResultsIn the base-case scenario, the incremental cost-effectiveness ratio (ICER) was NTD 811,050 per QALY gained. One-way sensitivity analyses showed that the model was sensitive to utilities and transition probabilities, but not particularly sensitive to the wastage assumption. In scenario analyses, the ICER was higher when applying the price for trastuzumab reference biologic (branded), than for trastuzumab biosimilar.ConclusionThe trastuzumab biosimilar combination regimen is cost-effective and offers significant drug cost savings in Taiwan.     

表柔比星联合多西他赛新辅助化疗治疗乳腺癌临床效果及对癌组织Ki-67表达的影响

目的 研究表柔比星(EPI)联合多西他赛(DOC)新辅助化疗治疗乳腺癌临床效果及其对患者癌组织细胞增殖核抗原(Ki-67)表达的影响.方法 选取我院于2018年1月至2019年3月收治的70例乳腺癌患者,将其随机分为对照组与观察组,每组各35例.两组均接受新辅助化疗,对照组采用5-氟尿嘧啶(5-FU)联合EPI治疗方案...     

多西他赛＋奈达铂＋方克联合同步放疗治疗局部晚期食管癌临床观察

目的：观察多西他赛＋奈达铂＋方克联合同步放疗治疗局部晚期食管癌的疗效和不良反应。方法：对106例局部晚期食管癌随机分组为两组：化放疗组（A组）,采用三维适形放疗,调强放疗同步TFP方案化疗4个周期。化疗用药多西他赛（国产艾素）50mg／m2,d1,静滴＋奈达铂60mg,d1-3,静滴＋方克1g,d1～3,静滴,放疗开始后第1、5、8、11周化疗;化疗同天放疗,采用三维适形放疗／调强放疗。单放组（B组）行单纯三维适形放疗／调强放疗。结果：化放疗组有效率87．5％,单纯放组有效率64％,化放疗组的有效率明显高于单放组（P〈0．05）;化放疗组1、2年生存率分别为82．1％、53．6％,单放组为56％、36％,化放疗组1、2年生存率明显高于单放组P〈0．05。结论：改良TFP方案联合同步放疗治疗局部晚期食管癌优于单纯放疗,可明显提高中晚期食管癌的疗效,放射性食管炎、骨髓抑制等毒副反应仍然偏高,但可耐受性,有一定治疗优势,值得在临床中进一步研究验证。     

多西他赛联合表阿霉素治疗晚期乳腺癌疗效观察

目的观察多西他赛联合表阿霉素治疗晚期乳腺癌的疗效及其不良反应。方法选取2010年1月～2011年1月本院收治的30例晚期乳腺癌患者,均给予多西他赛75mg/m2静脉滴注,第1天;表阿霉素75mg/m2静脉滴注,第1天。按21d为1个周期,至少2个周期化疗。结果 30例患者中,5例完全缓解,8例部分缓解,13例稳定,4例进展,有效率为43.3%。毒副反应主要以胃肠道反应和骨髓抑制为主。结论多西他赛联合表阿霉素治疗晚期乳腺癌具有较好的疗效和耐受性,可作为晚期乳腺癌的治疗方法。     

Docetaxel and bortezomib downregulate <Emphasis Type="Italic">Bcl-2</Emphasis> and sensitize PC-3-<Emphasis Type="Italic">Bcl-2</Emphasis> expressing prostate cancer cells to irradiation

Background  Currently, docetaxel is used to treat hormone-refractory metastatic prostate cancer. Docetaxel not only inhibits microtubule formation but can also downregulate expression of Bcl-2, a known antiapoptotic oncogene. Furthermore, the 26S proteasome inhibitor bortezomib can downregulate Bcl-2 expression. Previously, we demonstrated that overexpression of Bcl-2 renders cells resistant to radiation therapy. In this study, we investigated whether treating human prostate cancer cells with docetaxel, bortezomib, or both could modulate Bcl-2 expression and whether such modulation could render Bcl-2-overexpressing cells more susceptible to radiation. Methods  PC-3-Bcl-2 and PC-3-Neo human prostate cancer cells treated with docetaxel and/or bortezomib in addition to irradiation were analyzed in vitro for proliferation, clonogenic survival, cell cycle phase distribution, and expression of Bcl-2 and Bcl-xL proteins. Results  Docetaxel and bortezomib alone had significant cytotoxic effects. In addition, docetaxel, bortezomib, or radiation resulted in a G2M phase arrest in PC-3-Bcl-2, whereas only docetaxel or radiation did so in PC-3-Neo cells. Both cell lines were more sensitized to radiation’s killing effects when treated with the combination of docetaxel and bortezomib than when treated with either agent alone. Furthermore, docetaxel and bortezomib-treated cells exhibited marked changes in the expression of Bcl-2 and Bcl-xL. Conclusions  This is the first study to demonstrate that docetaxel and bortezomib in combination can effectively sensitize Bcl-2-overexpressing human prostate cancer cells to radiation effects by modulating the expression of key members of the Bcl-2 family. Together, these findings warrant further evaluation of the combination of docetaxel and bortezomib in prostate cancer.