Famitinib versus placebo in the treatment of refractory metastatic colorectal cancer:a multicenter,randomized,double-blinded,placebo-controlled,phaseⅡclinical trial

Background: Metastatic colorectal cancer(mCRC) patients with progressive disease after all available standard therapies need new medication for further treatment. Famitinib is a small-molecule multikinase inhibitor, with promising anticancer activities. This multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial was designed to evaluate the safety and efficacy of famitinib in mCRC.Methods: Famitinib or placebo was administered orally once daily. The primary endpoint was progression-free survival(PFS). Secondary endpoints included objective response rate(ORR), disease control rate(DCR), overall survival(OS), quality-of-life(QoL), and safety.Results: Between July 18,2012 and Jan 22,2014, a total of 167 patients were screened, and 154 patients were randomized in a 2:1 ratio to receive either famitinib(n = 99) or placebo(n = 55). The median PFS was 2.8 and 1.5 months in the famitinib and placebo groups(hazard ratio = 0.60,95% confidence interval = 0.41-0.86, P = 0.004). The DCR was 59.8% and 31.4%(P = 0.002) and the ORR was 2.2% and 0.0%(P = 0.540) in the famitinib and placebo groups,respectively. The most frequent grade 3-4 adverse events were hypertension(11.1%), hand-foot syndrome(10.1%),thrombocytopenia(10.1%) and neutropenia(9.1%). Serious adverse events occurred in 11(11.1%) patients in the famitinib group and 5(9.1%) in the placebo group(P = 0.788). The median OS of the famitinib and placebo groups was 7.4 and 7.2 months(P = 0.657).Conclusion: Famitinib prolonged PFS in refractory mCRC patients with acceptable tolerability.Trial registration This study was registered on ClinicalTrials.gov(NCT01762293) and was orally presented in the 2015 ASCO-Gastrointestinal

Famitinib in metastatic renal cell carcinoma： a single center study

Background Famitinib is a novel and potent multitargeting receptor tyrosine kinase inhibitor. The phase I clinical study showed that famitinib was well tolerated and had a broad anti-tumor spectrum. The purpose of this study was to examine the efficacy and safety of famitinib for the treatment of metastatic renal cell carcinoma （mRCC）. Methods The data of famitinib in treating patients with mRCC from the single-center phases I and II clinical trials were analyzed. Famitinib was administered orally at the dose of 13-30 mg once daily until tumor progression, occurrence of intolerable adverse reactions or withdrawal of the informed consent. Results A total of 24 patients with mRCC were treated including 17 patients at a dose of 25 mg once daily, 4 patients at a dose of 27 mg and 1 patient each at a dose of 13 rag, 20 mg and 30 mg, respectively. Twelve （50.0%） patients achieved partial response （PR） and 9 patients achieved stable disease （SD）. Progressive disease was found in 3 （12.5%） patients. The disease control rate was 87.5%. The median follow-up time was 17.6 months; the median progression free survival （PFS） was 10.7 （95% CI 7.0-14.4） months; and the estimated median overall survival （OS） time was 33.0 （95% CI 8.7-57.3） months. The adverse drug reactions mainly included hypertension （54.1%）, hand-foot skin reactions （45.8%）, diarrhea （33.3%）, mucositis （29.2%）, neutropenia （45.8%）, thrombocytopenia （29.2%）, hyperlipidemia （41.7%） and proteinuria （41.7%）. The incidence rate of grades 3 and 4 adverse events was low, mainly including hypertension 12.5%, hand-foot skin reactions 4.2%, neutropenia 4.2%, thrombocytopenia 4.2%, hyperlipidemia 4.2% and proteinuria 12.5%. Conclusions Famitinib has significant anti-tumor activity in mRCC. The common adverse reactions are generally manageable.

Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study

Background:Famitinib is a tyrosine kinase inhibitor against multiple targets,including vascular endothelial growth factor receptor 2/3,platelet-derived growth factor receptor,and stem cell factor receptor(c-kit).Previous studies have demonstrated anti-tumour activities of famitinib against a wide variety of advanced-stage solid cancers.We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy(CCRT)in patients with locoregionally advanced nasopharyngeal carcinoma(NPC).We also evaluated the feasibility of contrast-enhanced ultrasound(D-CEUS)as a predictor of early tumour response to famitinib and to correlate functional parameters with clinical efficacy.Methods:The trial was conducted in subjects with stage III or IVa-b NPC using a 3+3 design of escalating fami-tinib doses.Briefly,subjects received 2 weeks of famitinib monotherapy followed by 7 weeks of famitinib plus CCRT.D-CEUS of the neck lymph nodes was performed at day 0,8 and 15 after famitinib was administered before starting concurrent chemoradiotherapy.End points included safety,tolerability and anti-tumour activity.Results:Twenty patients were enrolled(six each for 12.5,16.5 and 20 mg and two for 25 mg).Two patients in the 25 mg cohort developed dose-limiting toxicities,including grade 4 thrombocytopenia and grade 3 hypertension.The most common grade 3/4 adverse events were leukopenia,neutropenia and radiation mucositis.D-CEUS tests showed that more than 60%of patients achieved a perfusion parameter response after 2 weeks taking famitinib alone,and the parameter response was associated with disease improvement.In the famitinib monotherapy stage,three patients(15%)showed partial responses.The complete response rate was 65%at the completion of treatment and 95%3 months after the treatment ended.After a median follow-up of 44 months,the 3-year progression-free survival(PFS)and distant metastasis-free survival were 70%and 75%,respectively.Subjects with a decrease of perfusion parameter response,such as peak intensity decreased at least 30%after 1 week of famitinib treatment,had higher 3-year PFS(90.9%vs.44.4%,95%CI 73.7%-100%vs.11.9%-76.9%,P<0.001)than those with an increase or a reduction of less than 30%.Conclusions:The recommended famitinib dose for phase II trial is 20 mg with CCRT for patients with local advanced NPC.D-CEUS is a reliable and early measure of efficacy for famitinib therapies.Further investigation is required to confirm the effects of famitinib plus chemoradiotherapy.

法米替尼治疗晚期实体瘤患者的药代动力学及安全性

目的:研究法米替尼15、20、25 mg剂量组在晚期实体瘤患者的药代动力学特征和安全性。方法:32例晚期或转移的实体瘤患者接受15、20、25 mg/d治疗,比较每个剂量组单次给药和多次给药后原型药物法米替尼及代谢物SHR116637的达峰时间(T_(max))、血药峰浓度(C_(max))等相关药代动力学的参数变化,观察治疗期间法米替尼在实体瘤患者中的不良事件/严重不良事件的发生率。结果:各剂量组单次给药后,血浆中法米替尼和代谢物SHR116637在6 h达峰,低、中、高剂量组t_(1/2)分别为(73.6±12.3)、(75.8±17.0)、(65.8±23.8)h;代谢物SHR116637的体内暴露量AUC_(0-24)、AUC_(0-t)和AUC_(0-∞)均随剂量增加而增加。多次给药后血浆中法米替尼及代谢物SHR116637 T_(max)与单次给药相比略有延迟。多次给药后法米替尼和代谢物SHR116637均有一定程度的蓄积,但以代谢物SHR116637中15 mg剂量组最明显,蓄积指数R_(AC_AUC)和R_(AC_Cmax)分别为6.45±2.82和5.37±2.39。单次给药阶段受试者无严重不良事件发生;在多次给药阶段共有2例受试者发生呼吸衰竭和心力衰竭。结论:单次给药后法米替尼在体内分布很广且消除较慢;多次给药后代谢物SHR116637有一定蓄积,3种剂量的法米替尼的安全性和耐受性良好。

苹果酸法米替尼联合同步放化疗治疗晚期鼻咽癌不良反应观察及护理

目的探讨苹果酸法米替尼联合同步放化疗治疗鼻咽癌患者不良反应及总结护理要点。方法对本院2011年11月-2013年12月20例局部晚期鼻咽癌患者采用苹果酸法米替尼联合同步放化疗,观察治疗过程患者不良反应发生情况及发生时间,并给予针对性对症处理。结果高血压、肾毒性、口腔黏膜炎、骨髓抑制、消化道反应、鼻出血、肝功能异常和手足皮肤反应发生率分别为60.0%、70.0%、90.0%、100.0%、85.0%、10.0%、45.0%和25.0%,给予对症处理后均能顺利完成治疗。结论苹果酸法米替尼联合同步放化疗治疗晚期鼻咽癌患者不良反应发生率较高,用药过程严密观察和监测患者用药后发生不良反应情况,及时处理,其可确保患者顺利完成治疗过程。

苹果酸法米替尼治疗转移性肾细胞癌的临床疗效观察(附9例报告)

目的探讨苹果酸法米替尼治疗转移性肾细胞癌的临床疗效。方法 2011年10月至2015年6月在第二军医大学长海医院接受法米替尼治疗并完成随访的转移性肾细胞癌9例,法米替尼25mg/d为起始剂量治疗,每日早餐前口服。42d为1个周期,观察肿瘤疗效及不良反应。结果 9例患者服药期间第3周期末获部分缓解6例、疾病稳定2例、疾病进展1例,客观缓解率为66.7%（6/9）。中位随访时间29个月（15-40个月）,中位无进展生存时间16.5个月（4.5-38.0个月）。不良反应以蛋白尿为主,其余与舒尼替尼相似。6例在治疗过程中因不良反应需减量或暂停服药,2例因反复不可耐受的蛋白尿终止治疗。结论法米替尼对转移性肾细胞癌患者具有良好的治疗效果,是一种不良反应可控的分子靶向药物,具有一定的临床应用前景。

转移性肾细胞癌患者护理管理

目的探讨苹果酸法米替尼首次用于转移性肾细胞癌患者的观察及护理。方法 2011年10月至2015年6月,泌尿外科接受新药苹果酸法米替尼治疗转移性肾细胞癌患者9例,通过随访过程中患者的不良反应发生情况及发生时间,研究护士给予相应的护理干预。结果白细胞降低、血小板降低、蛋白尿、手足综合征、贫血、高血压、食欲减退、腹泻、血尿、水肿和口腔黏膜炎发生率分别为88.9%、88.9%、88.9%、77.8%、66.7%、66.7%、66.7%、55.6%、33.3%、22.2%和22.2%,通过对症处理和护理干预,不良反应均处于可控范围内。结论苹果酸法米替尼治疗转移性肾细胞癌不良反应发生率较高,用药过程中严密观察和监测患者用药后的不良反应并及时护理,不仅保证用药的安全性,更使患者获得最大受益。

法米替尼在胃癌细胞MKN-45移植瘤中的作用

目的探讨法米替尼在胃癌细胞MKN-45移植瘤中的作用。方法胃癌细胞MKN-45移植瘤裸鼠共20只按随机数字法分为对照组、法米替尼50 mg/kg组、法米替尼100 mg/kg组、法米替尼500 mg/kg组,5只/组,分别给予0.9%氯化钠注射液和50、100、500 mg/kg法米替尼;每日1次,连续22 d,口服给药。筛选出高效低毒剂量(50 mg/kg)进行第2次动物实验,方法相同,MKN-45移植瘤裸鼠共40只随机分为8组(5只/组):对照组(0.9%氯化钠注射液,每日1次,连续18 d,口服给药);法米替尼组(50 mg/kg,每日1次,口服给药);5-氟尿嘧啶(5-FU)组(10 mg/kg和20 mg/kg组,隔天1次,腹腔注射);顺铂(DDP)组(3 mg/kg和6 mg/kg组,每周1次,腹腔注射);紫杉醇(PTX)组(10 mg/kg组,每周1次;以及20 mg/kg组:每周2次,每次10 mg/kg;腹腔注射),连续18 d。给药过程中,记录裸鼠生长状况、肿瘤体积、裸鼠体质量、结束后肿瘤组织称质量等用来计算肿瘤抑制率和死亡情况,进而评估药物疗效和安全性。通过免疫组织化学CD34染色检测法米替尼用药后肿瘤血管的变化。结果与对照组相比,法米替尼50 mg/kg组和法米替尼100 mg/kg组在给药第8天后裸鼠肿瘤体积明显生长减缓,用药22 d后,各组裸鼠肿瘤体积[对照组(2036±805)mm^3,法米替尼50 mg/kg组:(343±167)mm^3,法米替尼100 mg/kg组:(304±206)mm^3],差异有统计学意义(P<0.05)。给药第14日开始至给药结束,法米替尼100 mg/kg组裸鼠体质量较对照组和法米替尼50 mg/kg组明显下降,而对照组和法米替尼50 mg/kg组裸鼠体质量比较差异无统计学意义(P>0.05)。用药22 d后,各组裸鼠体质量:对照组(21.58±2.32)g,法米替尼50 mg/kg组:(18.78±1.41)g;法米替尼100 mg/kg组:(15.08±2.63)g。法米替尼50 mg/kg剂量将作为安全有效剂量继续第2次实验。第2次实验对比对照组和各化疗组,法米替尼用药后肿瘤体积和最终肿瘤质量均显著降低。法米替尼组抑瘤率为93.0%,远远高于其他单药组(5-FU组:10 mg/kg 16.6%,20 mg/kg组37.9%;DDP 3 mg/kg 54.3%,6 mg/kg 58.2%;PTX:10 mg/kg组22.9%,20 mg/kg组52.2%)。法米替尼组CD_(34)表达较对照组明显降低(法米替尼组CD_(34)^-;对照组CD_(34)^(++))。结论法米替尼较其他传统化疗药物对于胃癌有更好的抗肿瘤作用,为今后临床试验提供一定的理论支持。

苹果酸法米替尼Ⅰ期临床人体耐受性研究初步总结

目的:考察苹果酸法米替尼在人体的耐受性、最大耐受剂量并初步考察其抗肿瘤活性。方法:52例经细胞病理学证实的晚期肿瘤患者接受法米替尼治疗,每日一次口服。剂量范围:4～27 mg。28 d为一周期,每2周期评价抗肿瘤疗效。结果:51例可评价不良反应。对既往无高血压史的患者,25和27 mg均为安全剂量。如以治疗后4周作为确定剂量限制性毒性(DLT)的观察时间,法米替尼的DLT为Ⅲ度高血压和Ⅳ度血小板减少;如以治疗后8周作为DLT的观察时间,法米替尼的DLT则包括Ⅲ度高血压、Ⅳ度血小板减少、Ⅲ度蛋白尿和Ⅲ度甘油三酯升高。在25 mg剂量水平,其他的常见不良反应包括骨髓抑制、手足皮肤反应、乏力、口腔黏膜炎、疼痛、食欲减退、恶心、胆固醇升高、转氨酶升高、胆红素升高、外周感觉障碍等。48例可评价疗效2,5和27 mg组共8例PR,包括肾癌6例,GIST 1例,腺泡状软组织肉瘤1例。此外,各1例肝癌、脂肪肉瘤和胸腺癌患者未达PR,但PFS分别达12,12.7和17个月。结论:法米替尼是一个高效、不良反应可控的分子靶向药物,对无高血压史的患者2,5 mg是安全有效剂量,可作为Ⅱ期临床研究的推荐剂量。

采用生理药动学模型预测抗肿瘤新药法米替尼在人体中的药动学

建立并优化法米替尼的大鼠和猴的生理药动学模型,并且在该模型的基础上进行了种属外推至人,预测法米替尼在人体中的药动学和组织分布。根据文献和本实验室此前的实验结果以及ACD/ADME suite和Sim CYP软件预测法米替尼的理化性质,采用Gastro Plus软件的PBPK模块建立并优化法米替尼的大鼠和猴的生理药动学模型,并且进行种属外推至人,预测法米替尼在人体中的药动学和组织分布。优化好的大鼠和猴的生理药动学模型可以很好地预测大鼠和猴的药动学,大鼠和猴的AUC_(0-∞)实测值与计算值的比值分别为1.00和0.97。种属外推至人的AUC_(0-∞)的实测值与预测值的比值分别为1.63(大鼠→人)和1.57(猴→人)。法米替尼的大鼠和猴的生理药动学模型成功建立,并且在此基础上进行种属外推至人,能够很好地预测人体内的药动学行为,为今后的进一步研究药物-药物相互作用提供参考。