新药PF 299804 的相关文献

Pfizer is developing an orally available, potent, small molecule, panHER tyrosine kinase inhibitor, PF 299804, for the treatment of cancer. PF 299804 binds irreversibly to HER1, HER2 and HER4 tyrosine kinases. Clinical development is underway in patients with various cancer types in multiple countries, including the US, Canada, Japan, and countries in Europe and South America.

Key development milestones
Non-small cell lung cancer (NSCLC): A placebo-controlled phase III trial of PF 299804 in patients with stage IIIB or IV NSCLC refractory to standard therapy began in Canada in late 2009 (NCT01000025). Planned enrolment is 720 patients and the primary outcome measure is overall survival. Completion of the trial is projected for late 2012.

Pfizer has initiated a phase II trial (A7471017; NCT00818441) to assess the safety and efficacy of PF 299804 in patients with untreated adenoarcinoma of the lung. This trial is enrolling approximately 80 patients from sites in the US, Hong Kong and South Korea. Enrolment was continuing in February 2010.

In January 2008, Pfizer initiated a phase I/II trial (A7471003; NCT00553254) of PF 299804 in patients with advanced, refractory lung cancer, in South Korea. This single-arm, dose-escalation study will evaluate the efficacy of the drug in 80 patients with KRAS wild type advanced NSCLC which is refractory to chemotherapy and erlotinib or gefitinib. The study will also determine the recommended phase II dose for PF 299804. Dose escalation (once-daily) will continue until disease progression, unacceptable toxicity or withdrawal of consent. Preliminary results have been reported/1/. Pfizer reported in February 2010 that the study was continuing to recruit participants.

Also in January 2008, Pfizer initiated a phase II trial (A7471002; NCT00548093) of PF 299804 monotherapy in the US, in patients with advanced NSCLC, for whom treatment with at least one chemotherapy plus erlotinib was unsuccessful. The open-label, single group trial will enrol 74 patients who will be assessed for objective response rate over 6 months. Secondary outcome measures will be assessed over 6, 12 and 18 months. Pfizer reported in February 2010 that recruitment was continuing.

In November 2008, Pfizer initiated a phase II trial (A7471028; NCT00769067) in the US, Australia, Brazil, Canada, Hong Kong, Poland, Puerto Rico, Singapore, South Korea, Spain, Taiwan and the UK in patients with advanced NSCLC who have progressed after chemotherapy. The trial will enrol 160 patients who will be randomised to PF 299804 or erlotinib. The primary outcome measure is progression-free survival over 13 months. Recruitment of participants was continuing in February 2010; completion of the trial is anticipated by the end of 2010.

In February 2010, Pfizer initiated a US-based phase I trial to evaluate the molecular changes in tumour tissue after short-term exposure to neoadjuvant PF 299804 in patients with non-small cell lung cancer scheduled to undergo surgical resection (NCT00971191). The estimated study completion date is May 2011.

Glioblastoma: a phase II trial of PF 299804 in patients with relapsed/recurrent glioblastoma is projected to start in the US in mid-2010 (NCT01036477).

Head and neck cancer: in November 2008, Pfizer initiated a phase II open-label, single group trial (A7471027; NCT00768664) in Canada, in patients with recurrent or metastatic head and neck squamous cell cancer. The trial will enrol 56 patients patients who have not yet received any other drug treatment for this condition. The primary outcome measure will be the best overall response rate at 18 months. The trial is expected to be completed in 2011.

Solid tumours: a phase I, open-label, single group phase I trial (A7471005; NCT00783328) was initiated in Japan in November 2008, in patients with advanced solid tumours. The trial will enrol 12 patients, and the primary outcome measure will be safety. The study was continuing in February 2010; enrolment of patients has been completed.

In June 2008, Pfizer initiated a US-based, phase I, open-label, single group trial (A7471004; NCT00728390) of oral PF 299804 in combination with intravenously administered figitumumab, in patients with advanced solid tumours. The trial is enrolling 65 patients at sites in the US, France and Spain who will be assessed for safety over 18 months. Enrolment was reported to be continuing in February 2010.

A phase I trial to investigate the effect of PF 299804 on the pharmacokinetics of dextromethorphan in patients with advanced malignant solid tumours began in September 2008 (NCT00728468). Enrolment was continuing in February 2010; study completion is anticipated during 2010.

In October 2005, Pfizer initiated a phase I, open-label, single group trial (A7471001; NCT00225121) in the US and the Netherlands, in patients with advanced, malignant solid tumours. The trial has enrolled 120 patients and is assessing safety, pharmacokinetics and pharmacodynamics. The study was reported to be continuing in February 2010.

Healthy volunteers: Pfizer conducted an open-label, single- radiolabeled dose, phase I study (NCT01034748) to investigate the absorption, metabolism and excretion of PF 299804 in six healthy male volunteers. The trial was completed in February 2010.

Pharmacology Overview:
Pharmacodynamics:
  Inhibits EGFR-MAPK signalling pathway and reduces Ki67 proliferation marker; PF 299804 resistance overcome by co-administration with MET kinase inhibitors
  Mechanism of action:
  Protein tyrosine kinase inhibitors
   Protein kinase inhibitors
   Protein tyrosine kinase modulators
   Protein kinase modulators
   Phosphotransferase (Alcohol Group Acceptor) inhibitors
   Phosphotransferase (Alcohol Group Acceptor) modulators
   Phosphotransferase inhibitors
   Phosphotransferase modulators
   Transferase inhibitors
   Transferase modulators
   Enzyme inhibitors
   Enzyme modulators
  Activity versus parent drug: unspecified parent

Clinical Overview:
Route(s) of Administration: PO
  Administration Freq.(per day):
  Drug Interactions:
  Unknown.

Adverse Events:
In a phase I/II study of PF 299804 in patients with advanced non-small cell lung cancer after failure of at least one chemotherapy and erlotinib, the most common Grade 3 adverse events included skin disorders (15.1%) and diarrhea (13.2%). Three patients experienced Grade 4 pulmonary embolus/dyspnea, which may have been treatment- related/2/.

Daily administration of PF 299804 (0.5-60mg) was tolerable and safe, in a phase I trial in patients with advanced solid tumours. The most commonly reported adverse events (AEs) of any grade were diarrhoea (78%) and rash (65%). PF 299804 was found to produce these AEs in a significant dose- or exposure-dependent manner. A total of 3/6 patients who received PF 299804 60 mg experienced a dose-limiting toxicity (DLT) of hand-foot syndrome, dehydration related to diarrhoea, and mucositis, respectively. The 23 patients who received the 45mg dose experienced grade 3 fatigue, DVT, nausea, acne, hypokalaemia, diarrhoea, hypoxia and decreased appetite. Grade 4 toxicities experienced by these patients were dyspnea, pulmonary embolism and pain/1/ /3/ /4/.

Pharmacokinetics:
The C sub(max) and AUC values of PF 299804 increased with dose in an approximately linear manner, in a phase I trial in patients with advanced solid tumours. A suggested terminal half-life value of >24 hr was observed/4/. Further analysis revealed an average terminal half- life of ~85 hours. At the recommended phase II dose (45mg/day), the mean steady-state trough concentration approached the predicted human efficacious concentration/1/. Patients received 0.5-60mg daily.
Pharmacodynamics (Cancer):
Clinical studies: in a phase I trial in patients with advanced solid tumours, daily administration of PF 299804 (0.5-60mg) resulted in the mechanistic inhibition of the EGFR-MAPK signalling pathway, and reduced the Ki67 proliferation marker/1/.
Preclinical studies: in preclinical studies, HCC827 cells were exposed to increasing concentrations of PF 299804 to generate resistant cell lines HCC827 PFRs. The growth of HCC827 PFR cells was inhibited only with the combination of PF 299804 and the MET kinase inhibitor PF 2341066 both in vitro and in vivo, but not by either agent alone, suggesting that resistance was caused by MET amplification/5/.

Therapeutic Trials:
Cancer:
PF 299804 demonstrated clinical and biological activity in a phase I/II study patients with advanced non-small cell lung cancer after failure of at least one chemotherapy and erlotinib. A total of 53 patients were enrolled into two study arms: adenocarcinoma (n = 43) and non-adenocarnioma (n = 6), and treated with PF 299804 (45 mg/day). Among the 43 evaluable patients, three patients achieved a partial response and 26 patients achieved stable disease at >=6 weeks, as measured by RECIST. Additionally, seven patients treated with PF 299804 experienced clinical benefit, as defined by partial response plus stable disease >=6 months, including 5 adenocarcinoma and 2 non- adenocarcinoma patients/2/ /3/ /4/ /1/.

References:
1. Schellens J, Guo F, et al. First-in-human study of PF-00299804 in advanced cancer patients: correlation between pharmacokinetics and pharmacodynamics. 20th-EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. : 177-178 abstr. 564, 24 Oct 2008. Available from: URL: http://www.ecco-org.eu. (English).
2. Pfizer. Pfizer Presents Data With Novel Investigational Agents In Select Patient Groups With Non-Small Cell Lung Cancer. Media Release. : 31 May 2009. Available from: URL: http://www.pfizer.com. (English).
3. Janne PA, Schellens JH, et al. Preliminary activity and safety results from a phase I clinical trial of PF-00299804, an irreversible pan-HER inhibitor, in patients with NSCLC. 44th Annual Meeting of the American Society of Clinical Oncology. : abstr. 8027, 30 May 2008. Available from: URL: http://www.asco.org. (English).
4. Schellens JH, Britten CD, et al. First-in-human study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-00299804, a small molecule irreversible panHER inhibitor in patients with advanced cancer. Journal of Clinical Oncology. 25 (Suppl.): 162, No. 18, Part 1, 20 Jun 2007. (English).
5. Zejnullahu K, Song YC, et al. MET amplification leads to resistance to the irreversible EGFR inhibitor PF00299804 through selection of a pre-existing MET amplified clone. 100th Annual Meeting of the American Association for Cancer Research. : abstr. 3874, 21 Apr 2009. Available from: URL: http://www.aacr.org. (English).

最新的进展是在加拿大进行的III期非小细胞肺癌临床试验。
这药的最常见副作用也是皮疹和腹泻。

翻译好再看

辉瑞公司正在开发可口服，强效，小分子，panHER酪氨酸激酶抑制剂，PF 299804，用于治疗癌症。犯规299804不可逆转的HER1，HER2和HER4酪氨酸激酶结合。临床开发是在多个国家的不同类型的癌症，包括美国，加拿大，日本，和欧洲和南美国家的患者正在。

重点发展的里程碑
非小细胞肺癌（NSCLC）：一个安慰剂对照的III期试验的PF 299804 IIIB期或IV期非小细胞肺癌的标准治疗难治性的患者开始在加拿大在2009年年底（NCT01000025）。计划招生720例，主要结果测量是整体存活率。试验完成后，预计2012年年底。

辉瑞公司已经发起了第二阶段试验（A7471017; NCT00818441）评估在与未经治疗的肺adenoarcinoma患者的安全性和疗效的PF 299804。这项试验是在美国，香港和韩国的网站招收约80例。报名仍在继续2010年2月。

在2008年1月，辉瑞公司发起的一个阶段I / II期试验（A7471003; NCT00553254）先进，难治性肺癌患者的PF 299804，在韩国。这单臂，剂量递增研究将评估药物的疗效，在KRAS基因野生型晚期非小细胞肺癌是难治性化疗和厄洛替尼或吉非替尼的患者80例。这项研究也将确定推荐相犯规299804第二剂量。剂量升级（每日一次）将继续下去，直到病情恶化，不可接受的毒性或撤销同意。初步结果已报/ 1 /。辉瑞公司于2010年2月报道，这项研究是继续招募参加者。

此外，在2008年1月，辉瑞开始了第二阶段试验（A7471002; NCT00548093）PF 299804单一疗法在美国，在晚期非小细胞肺癌患者，其中至少有一个化疗加厄洛替尼治疗失败。开放标签，单组试验，将招收74人将被评​​估的客观反应率超过6个月的患者。 6，12和18个月将评估次要结局措施。辉瑞公司于2010年2月报道，招聘工作仍在继续。

在2008年11月，辉瑞公司发起了II期临床试验（A7471028; NCT00769067）在美国，澳大利亚，巴西，加拿大，香港，波兰，波多黎各，新加坡，韩国，西班牙，台湾和英国，在晚期非小细胞肺癌患者化疗后有进展。该试验将招收160人将随机PF 299804或厄洛替尼的患者。主要结果测量是无进展生存期超过13个月。招募参与者继续在2010年2月，预计2010年底完成审判。

2010年2月，辉瑞公司发起的总部设在美国的I期临​​床试验，评估后，短期暴露在非小细胞肺癌癌，接受手术切除（NCT00971191）患者新辅助犯规299804在肿瘤组织中的分子变化。估计研究的完成日期是2011年5月。

胶质母细胞瘤患者复发/经常性胶质母细胞瘤是预计在2010年年中（NCT01036477）在美国开始的第二阶段试验的PF 299804。

头部和颈部癌症，于2008年11月，辉瑞公司发起第二阶段的开放标签，单组试验（A7471027; NCT00768664）复发或转移性头颈部鳞状细胞癌患者在加拿大，。该试验将招收56例患者尚未收到此条件的任何其他药物治疗的患者。主要结果测量将是最好的整体回应率在18个月。审判预计将在2011年完成。

实体瘤：I期，开放标签，单组阶段我试验（A7471005; NCT00783328）在日本发起，于2008年11月，在晚期实体瘤患者。该试验将招收12名患者，主要结果测量将是安全的。这项研究是在2010年2月继续;病人的入学率已经完成。

在2008年6月，辉瑞公司发起，总部设在美国，第一阶段，开放标签，单组试验;结合口服犯规299804与静脉注射figitumumab，晚期实体瘤患者（A7471004 NCT00728390）。该试验是在美国，法国和西班牙将超过18个月的安全评估网站招收65例。报名将在2010年2月持续报道。

一个I期临床试验到晚期恶性实体瘤患者的PF 299804右美沙芬的药代动力学研究开始于2008年9月（NCT00728468）。报名继续在2010年2月，研究完成后，预期在2010年。

在2005年10月，辉瑞公司发起了一个阶段的我，开放标签，单组试验（A7471001; NCT00225121）在美国和荷兰，先进，恶性实体瘤患者。该试验已招收了120名病人，并正在评估安全性，药代动力学和药效学。这项研究报告将在2010年2月继续。

健康志愿者：辉瑞公司进行的开放标签，放射性标记的单剂量，I期研究（NCT01034748）调查，在6名健康男性志愿者的吸收，代谢和排泄犯规299804。该试验是在2010年2月完成。

药理概述：
药效学：
  抑制EGFR - MAPK信号转导通路，并降低Ki67的增殖标记; PF 299804阻力，克服共同管理的MET激酶抑制剂
  作用机制：
  酪氨酸蛋白激酶抑制剂
   蛋白激酶抑制剂
   酪氨酸蛋白激酶调制器
   蛋白激酶调制器
   磷酸（酒精组接受器）抑制剂
   磷酸（酒精组接收器）调制器
   磷酸酶抑制剂
   磷酸调制器
   转移酶抑制剂
   转移调制器
   酶抑制剂
   酶调制器
  活动与母体药物：未指定的父

临床概述：
路线（S）管理：PO
  管理频率（每天）。
  药物相互作用：
  未知。

不良事件：
在阶段I / II的PF 299804研究与至少一个化疗和厄洛替尼失败后的晚期非小细胞肺癌患者，最常见的3级不良事件包括皮肤疾病（15.1％）和腹泻（13.2％） 。三名病人经历了四级肺栓塞/呼吸困难，它可能已被处理相关/ 2 /。

PF的299804（0.5 - 60mg）的日常管理，容忍和安全，在晚期实体瘤患者的I期临床试验。任何等级的最常见的不良事件报告（AES），腹泻（78％）和皮疹（65％）。 299804犯规被发现在一个显著的剂量或暴露依赖性产生这些不良。共3 / 6的病人谁收到PF 299804 60毫克的手足综合征，腹泻脱水，粘膜炎，分别经历了剂量限制性毒性（DLT）。收到45mg剂量的23例患者经历了3级的疲劳，深静脉血栓形成，恶心，痤疮，低钾血症，腹泻，缺氧和食欲下降。四级经历毒性这些病人呼吸困难，肺栓塞和疼痛/ 1 / / 3 / / 4 /。

药代动力学：
c子（max）和AUC值的PF 299804的增加与剂量近似线性的方式，在晚期实体瘤患者的I期临床试验。观察/ 4 /建议终末半衰期> 24小时值。进一步分析发现，平均码头〜85小时的半衰期。在建议的第二阶段剂量（45mg/day），平均稳态谷浓度接近预测人类有效浓度/ 1 /。患者接受每天0.5 - 60mg。
药效学（癌症）：
临床研究：在晚期实体瘤患者的日常管理，PF的299804（0.5 - 60mg）的I期临床试验结果在机械的EGFR - MAPK信号通路的抑制作用，并降低Ki67的增殖标记/ 1 /。
临床前研究：在临床前研究，HCC827细胞暴露于299804 PF的浓度的增加，产生耐药细胞株HCC827 PFRs。 HCC827 PFR细胞的生长受到抑制，只能用相结合的PF 299804和MET扩增/ 5 / MET激酶抑制剂PF在体外和体内，而不是由单独或者代理2341066，表明电阻造成的。

治疗性试验：
巨蟹座：
PF 299804显示，在至少一个化疗和厄洛替尼失败后的晚期非小细胞肺癌I / II期研究的患者的临床和生物活性。共有53名患者被纳入到两个研究武器：腺癌（N = 43）和非adenocarnioma（N = 6），犯规299804（45毫克/天）治疗。其中43例可评估患者中，有3例，取得了部分反应，26例，取得了> = 6周病情稳定，测量的RECIST。此外，与PF 299804经验丰富的临床获益治疗的患者，部分反应，加上稳定的疾病定义> = 6个月，包括5腺癌和非腺癌患者2 / 2 / / 3 / / 4 / / 1 /。

参考文献：
1。 Schellens J，郭楼等。首先，在人类研究中晚期癌症患者的PF - 00299804：药代动力学和药效学之间的关联。 20 - EORTC - NCI - AACR分子靶标和癌症治疗研讨会。 ：177-178 abstr。 564，2008年10月24日。可从以下网址：http://www.ecco-org.eu。 （英文）。
2。辉瑞。辉瑞公司提出了新的研究性代理在选择与非小细胞肺癌患者组的数据。媒体发布。 2009年5月31日。可从以下网址：http://www.pfizer.com。 （英文）。
3。几套PA，Schellens JH，等。初步活动和安全结果我从一个阶段的临床试验的PF - 00299804，一个不可逆转的泛她的抑制剂，在非小细胞肺癌患者。美国临床肿瘤学会第44届年会。 ：abstr。 8027，2008年5月30日。可从以下网址：http://www.asco.org。 （英文）。
4。 Schellens建华，布里顿的CD，等。首先，在人类研究的安全性，耐受性，药代动力学，PF - 00299804，在晚期癌症患者的一种小分子的不可逆panHER抑制剂药效。临床肿瘤学杂志。 25（增刊）：162，第18号，2007年6月20日，第1部分。 （英文）。
5。 Zejnullahu钾，宋永昌，等。 MET扩增导致耐药性不可逆的表皮生长因子受体抑制剂PF00299804通过选择一个预先存在的MET的扩增克隆。美国癌症研究协会第100届年会。 ：abstr。 3874，2009年4月21日。可从以下网址：http://www.aacr.org。 （英文）。

这药的正式名字叫Dacomitinib。

老马 发表于 2011-10-2 20:41

                               
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这药的正式名字叫Dacomitinib。

谢谢老马，学习了。

谢谢， 学习了

感谢分享！

这个药也是EGFR抑制剂（抑制EGFR - MAPK信号转导通路），不知对特，易耐药后的治疗有多大效果。

临床试验的结果呢？

缺少最新资料！

此药有最新进展吗？