Pan-Her不可逆抑制剂NOV120101 (Poziotinib)(HM781-36B)

多谢马哥。

Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models.
http://www.ncbi.nlm.nih.gov/pubmed/21732342
Abstract
The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781-36B. The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781-36B is the most potent pan-HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.

Phase I study to evaluate the safety and to assess the food effect of HM781-36B, a
novel pan-HER inhibitor continuously given in patients with advanced solid tumors.
YuJung Kim, Jisu Oh, Tae Min Kim, Sae-Won Han, Keun Wook Lee, Jee Hyun Kim, Seock-Ah Im,
Kyun-Seop Bae, Yook-Hwan Noh, Hyun-Jin Nam, Kyung-Mi Park, Jeewoong Son, Yung-Jue Bang;
Background: HM781-36B, a novel pan-HER tyrosine kinase inhibitor, showed potent in vitro and in vivo
antitumor activities for EGFR mutant models including T790M mutation. In the previous 2-weeks on,
1-week off phase I study, the maximum tolerated dose (MTD) was determined as 24 mg/day. Phase I study with a continuous daily dosing schedule was conducted to determine the recommended dose (RD), and to assess the effect of food on pharmacokinetics (PK) in patients (pts) with advanced solid tumors.
Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 313 scheme was used in the dose escalation study, and additional 8 patients were enrolled to test food effects. Results: 20 pts (median age: 55 years [range32-77], M:F513:7, ECOG PS 0/1/2/3 8/12/0/0) were enrolled (5 NSCLC, 4 colon cancer, 3 stomach cancer, 2 breast cancer, 2 rectal cancer, 2 common bile duct cancer, 1 pancreatic cancer and 1 esophageal cancer); 12 in the dose escalation and 8 in the food effect study cohort. Twelve pts were heavily pretreated($4 regimens). Dose limiting toxicities (DLTs) were G3 anorexia in 1 pt at 18mg/day, G3 diarrhea and anorexia in 1 pt, and drug compliance ,80% due to G2 adverse events in 1 pt at 24mg/day. The MTD was determined as 18 mg/day, and RD was determined as 16 mg/day. The most common drug-related adverse events were diarrhea, stomatitis, skin rash, paronychia, pruritus and anorexia. Among 16 evaluable pts, 4 achieved partial responses (PR)[1 NSCLC, 2 breast cancer, 1 common bile ductcancer], and the duration of response were 32, 40+, 21, and 8 weeks, respectively. Five pts had stable disease (SD). The median duration of treatment in pts with PR or SD was 33.5 weeks (range, 15-82). Under both fasted and fed condition, there were no significant differences of AUClast values, whereas Cmax values were lower in fed condition than in fasted condition.
Conclusions: Continuous daily dosing schedule of HM781-36B is safe and well tolerated in advanced solid tumors. It exerts anticancer activity, without being influenced by food. Updated data will be presented at the meeting. Clinical trial information:NCT01455584.

一个新型pan-HER抑制剂HM781-36B在晚期实体肿瘤中应用的Ⅰ期临床试验（续）
　　背景：HM781-36B是一个pan-HER酪氨酸酶抑制剂，对吉非替尼或厄洛替尼耐药性EGFR L858R/T790M双突变细胞有强烈的抑制作用。在服用14天/停用14天的1期临床试验中，最大剂量（MTD）确定为每天24mg，接着进行了连续每天服用方案的晚期实体肿瘤临床试验，以确定推荐剂量，以及调查食物对药代动力学的影响。
     方法：符合入组条件的患者为标准治疗无效或者进展的晚期恶性肿瘤患者。在剂量递增研究采用标准3+3模式，额外8例患者被纳入食物测试组。
     结果：20例患者[中位年龄：55（32～77）岁，男性/女性：13/7例，平均化疗次数：4次，ECOG PS 0/1/2/3：8/2/0/0例，5例非小肺癌，4例肠癌，4例胃癌，2例乳腺癌，2例直肠癌，2例胆总管癌，1例胰腺癌，1例食管癌。剂量限制性毒性（DLT）状况为：1例3级厌食（18mg每天组），1例3级腹泻和3级厌食，1例80%的2级副作用（24mg每天组）。最大耐受剂量确定为18mg每天，推荐剂量为16mg每天。最常见的副作用为：腹泻，口腔炎，皮疹，甲沟炎，皮肤瘙痒，厌食。在16例可评估患者中，4例患者得到部分缓解（1例非小肺癌，2例乳腺癌，1例胆总管癌），有效时间各为32周，40+周，21周和8周。5例患者疾病稳定。中位疾病控制时间为33.5周（15-82周）。空腹和进食对药代动力学无显著性差异，空腹的最大血药浓度比进食组略高。
      结论：连续每天服用HM781-36B在晚期实体瘤中应用安全且耐受性好。研究已经观察到HM781-36B抗肿瘤活性的初步证据。进食对HM781-36B无影响。

谢谢老马, MARK起来

老马，你在群里说基本搞定了，是什么意思？
是否是易耐药后的最佳选择呢？到时候出来药不知道价格是否可以承受的了？

后续的都有机会了，大家继续

Title: Population Pharmacokinetic Analysis of a novel pan-HER inhibitor, HM781-36B, in Patients with Advanced Malignant Solid Tumors
Authors: Yook-Hwan Noh* (1), Hyeong-Seok Lim (1), Kyun-Seop Bae (1)
Institutions: (1) Ulsan University College of Medicine, Asan Medical Center, Seoul, Korea
Objectives: HM781-36B is an orally active inhibitor of human epidermal growth factor receptors HER1, HER2, and HER4 tyrosine kinase. The objectives of this work were to quantitatively describe the pharmacokinetic (PK) characteristics of HM781-36 in Phase I oncology patients and to evaluate the potential sources of its PK variability.
Methods: The HM781-36 population PK analysis were performed using the data from three phase I clinical studies, which included 1933 HM781-36 plasma concentrations from 58 patients with advanced solid cancers (101 PK study: 39 patients, 102 PK study: 11 patients, 102 food effect PK study: 8). In 101 PK study, HM781-36B was administered once-daily oral doses ranged from 0.5 to 32 mg (0.5, 1, 2, 4, 8, 12, 16, 20, 24 and 32 mg/day) and were given for 14 days. Blood samples for PK were collected up to 24 hr on the first dosing day and up to 48 hr after the last dosing. In 102 PK and 102 food-effect studies, HM781-36B was administered with once-daily oral doses ranged from 12 to 24 mg (food effect study – 16 mg only) and was given for 28 days. Blood samples for PK were collected up to 24 hr on the first and last dosing day. Plasma HM781-36 concentrations were analyzed using liquid chromatography-mass spectrometry. PK analyses were performed by non-compartment method, as well as compartmental method. Nonlinear mixed effects modeling for the population pharmacokinetic analysis of HM781-36 was performed using NONMEM version 7.2 with ADVAN2 subroutine and a combined exponential and additive error model to estimate the residual unexplained error. The model selection was based on the generated objective function value (OFV) and diagnostic plots. The robustness of the final model was evaluated using a bootstrap procedure and model stability and appropriateness using numerical and visual predictive checks.
Results: A one-compartment model with first order absorption and mixed residual error model best described the pharmacokinetic data. The final base model predicted a population apparent clearance (CL/F) of HM781-36 of 16.74 L/hr. The absorption rate constant, central volume of distribution, and apparent clearance were 1.69 hr-1 (between-subject variability, BSV: 10.7%), 120 L (BSV: 4.8%), and 16.7 L/hr (BSV: 4.3%), respectively. The model fitted well with the observed data, and the bootstrap and predictive checks guaranteed robustness and appropriateness of the population pharmacokinetic model. No significant relationship was observed between PK parameters and patient demographics.
Conclusions: A population pharmacokinetic model for HM781-36 in patients with advanced malignant solid tumors has been developed. This model will be used as HM781-36 basic drug model for dose individualization and adjustment and for designing later Phase II and III clinical trials. This study provided a rationale for further clinical evaluation of HM781-36B.
References:
[1] JaeWoo Kim, Kyun-Seop Bae. Pharmacokinetics of the pan-HER inhibitor, HM781-36B, in patients with advanced malignant solid tumors (Abstract), JSCPT-KSCPT-ASCPT Joint conference 2011 and the 32nd JSCPT Annual Scientific meeting.

mark

Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)Piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein
http://ip.com/patfam/en/48044309
WO 2013051883 A2