A Prospective, Multicentre, Uncontrolled, Phase Ib/II Study of LY2780301 in Combination With Weekly Paclitaxel in HER2-negative Metastatic or Locally Advanced Breast Cancer in Patients With and Without PI3/AKT/S6 Pathway Activation. - TAKTIC-IPC 2012-008

The overall rationale of this study evaluating tolerance and efficacy of LY2780301 in combination with paclitaxel in HER2-negative, inoperable locally advanced or metastatic breast cancer (MBC) is based on :
the medical need in this population with either hormonal-resistant or unsensitive and/or rapidly progressive disease
the preclinical evidences for involvement of PI3K/AKT pathway in tumor progression and drug resistance, including taxanes as well as its potential reversion by AKT inhibition
the high level of frequency of PI3K/AKT activation in HER2-negative MBC
the in vitro and in vivo preclinical activity of LY2780301, and its synergistic combination with various anticancer agents, including taxanes
the favourable profile of tolerance of LY2780301 in phase I trial
Weekly paclitaxel is conventionally administered at 80 mg/m²/week and is a standard treatment in breast cancer (BC) As described above, LY2780301 500 mg once daily has been established as the RP2D in phase I single agent trial.
Evidence of pharmacodynamic activity was noted at 400-500 mg QD. Conservatively, the first dose level to be explored will be LY2780301 400 mg QD and paclitaxel 70 mg/m²/week.

开始日期2014-01-01

申办/合作机构

Institut Jean Paoli & Irene Calmettes

NCT02018874

/ Completed临床1期IIT

A Phase Ib, Open-label, Dose Escalation Study of the Safety, Tolerability and Efficacy of LY2780301 (a p70/AKT Inhibitor) in Combination With Gemcitabine in Patients With Advanced or Metastatic Cancer

In the First-in-Human, JWAA trial, the LY2780301 displayed a favourable safety profile, a high pharmacokinetic exposure and the ability to decrease pS6. LY2780301 has shown synergistic activity in combination with targeted agents or chemotherapy including gemcitabine. We propose herein to combine LY2780301 with gemcitabine and to treat different tumor types with molecular alterations. This may validate the anti-tumor activity of the LY2780301 and it will increase our knowledge regarding molecular predictors of its efficacy.

开始日期2013-09-01

申办/合作机构

Gustave Roussy, Cancer Campus, Grand Paris

NCT01115751

/ Completed临床1期

A Phase I Trial of Single-Agent LY2780301 in Patients With Advanced or Metastatic Cancer

Study JWAA is a multicenter, nonrandomized, open-label, dose-escalation Phase 1 study of oral LY2780301 in patients with advanced solid tumors.

开始日期2010-03-01

申办/合作机构

Eli Lilly & Co.

100 项与 LY-2780301 相关的临床结果

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100 项与 LY-2780301 相关的转化医学

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100 项与 LY-2780301 相关的专利（医药）

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项与 LY-2780301 相关的文献（医药）

2022-05-01·Molecular oncology2区 · 医学

Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study

2区 · 医学

ArticleOA

作者: Pakradouni, Jihane ; Dalenc, Florence ; Goncalves, Anthony ; Isambert, Nicolas ; Bertucci, François ; Robert, Marie ; Garnier, Séverine ; Carbuccia, Nadine ; Mamessier, Emilie ; Chaffanet, Max ; Adelaïde, José ; Sfumato, Patrick ; Guille, Arnaud ; Levy, Christelle ; Sabatier, Renaud ; Vicier, Cécile

The phosphatidylinositol‐3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2‐negative breast cancer and may play a role in taxane resistance. The phase IB/II TAKTIC trial (NCT01980277) has shown that combining a dual AKT and p70 ribosomal protein S6 kinase (p70S6K) inhibitor (LY2780301) taken orally with weekly paclitaxel in HER2‐negative advanced breast cancer is feasible, with preliminary evidence of efficacy. We wanted to explore whether circulating tumor DNA (ctDNA) may be a surrogate marker of treatment efficacy in this setting. Serial plasma samples were collected and cell‐free DNA was sequenced using low‐coverage whole‐genome sequencing, and analysis was completed with droplet digital polymerase chain reaction (PCR) for some patients with driver mutations. Baseline tumor fraction (TF) and TF after 7 weeks on treatment were compared to progression‐free survival (PFS) and the overall response rate. We also explored circulating copy number alterations associated with treatment failure. Of the 51 patients enrolled in the TAKTIC trial, at least one plasma sample was available for 44 cases (96 timepoints). All patients with tumor TP53, PI3KCA, or AKT1 mutations harbored at least one of these alterations in plasma. TF at inclusion was correlated with PFS (6m‐PFS was 92% for ctDNAneg patients vs 68% for ctDNApos cases; hazard ratio [HR] = 3.45, 95% confidence interval [CI] [1.34–8.90], P = 0.007). ctDNA status at week 7 was not correlated with prognosis. Even though most circulating copy number alterations were conserved at disease progression, some genomic regions of interest were altered in post‐progression samples. In conclusion, ctDNA detection at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma‐based copy number analysis may help to identify alterations involved in resistance to treatment.

2021-12-01·European journal of cancer (Oxford, England : 1990)1区 · 医学

TAKTIC: A prospective, multicentre, uncontrolled, phase IB/II study of LY2780301, a p70S6K/AKT inhibitor, in combination with weekly paclitaxel in HER2-negative advanced breast cancer patients

1区 · 医学

Article

作者: Charafe-Jauffret, Emmanuelle ; Sabatier, Renaud ; Dalenc, Florence ; Robert, Marie ; Garnier, Séverine ; Gonçalves, Anthony ; Bertucci, François ; Isambert, Nicolas ; Chaffanet, Max ; Rezai, Keyvan ; Sfumato, Patrick ; Levy, Christelle ; Carbuccia, Nadine ; Guille, Arnaud ; Boher, Jean M ; Birnbaum, Daniel ; Vicier, Cecile ; Pakradouni, Jihane ; Popovici, Cornel ; Provansal, Magali ; Adélaïde, José

BACKGROUND:

Hormone-resistant HER2-negative or triple-negative advanced breast cancers (ABC) are routinely treated with paclitaxel chemotherapy. LY2780301 is a dual inhibitor of p70 ribosomal protein S6 kinase and AKT. The TAKTIC study aimed at exploring the combination of paclitaxel and LY2780301 in this population.

METHODS:

In this multicentric phase Ib/II trial, we enrolled patients with HER2-negative ABC, with (phase IB) or without (phase II) prior to cytotoxic treatment for advanced disease. Oral LY2780301 was administered once daily in combination with intravenous weekly paclitaxel. Primary endpoints were to determine the recommended phase II dose (RP2D) of the combination of LY2780301 with weekly paclitaxel (phase Ib), and to estimate a 6 months objective response rate (ORR) (phase II) in patients with HER2-negative ABC, both in the overall patient population and in cases with activation of the PI3K/AKT pathway (PI3KAKT+).

RESULTS:

A total of 51 patients were enrolled; RP2D was LY2780301 500 mg QD+ paclitaxel 80 mg/m². Main drug-related adverse events noted in phase Ib included neuropathy (75% of patients, grade 3-4 in 8%), asthenia (58% of patients, no grade 3-4), and ungual toxicity (50% of patients, grade 3-4 in 25%). They were similar in the phase II part, except that 14% of patients experienced pneumonia (grade 3-4 in 6%). In the phase II part, 6-month ORR in the overall population and in PI3KAKT+ subgroup were, respectively, 63.9% [48.8-76.8] and 55% [35-73.7].

CONCLUSION:

Combining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup.

TRIAL REGISTRATION ID:

NCT01980277.

2017-11-01·Cancer prevention research (Philadelphia, Pa.)

Targeting Aberrant p70S6K Activation for Estrogen Receptor–Negative Breast Cancer Prevention

Article

作者: Brady, Samuel W. ; Yao, Jun ; Zhang, Qingling ; Yu, Dihua ; Wang, Jinyang ; Arun, Banu ; Wang, Xiao ; Seewaldt, Victoria L.

Abstract:

The prevention of estrogen receptor–negative (ER−) breast cancer remains a major challenge in the cancer prevention field, although antiestrogen and aromatase inhibitors have shown adequate efficacy in preventing estrogen receptor–positive (ER+) breast cancer. Lack of commonly expressed, druggable targets is a major obstacle for meeting this challenge. Previously, we detected the activation of Akt signaling pathway in atypical hyperplasic early-stage lesions of patients. In the current study, we found that Akt and the downstream 70 kDa ribosomal protein S6 kinase (p70S6K) signaling pathway was highly activated in ER− premalignant breast lesions and ER− breast cancer. In addition, p70S6K activation induced transformation of ER− human mammary epithelial cells (hMEC). Therefore, we explored the potential of targeting Akt/p70S6K in the p70S6K activated, ER− hMEC models and mouse mammary tumor models for the prevention of ER− breast cancer. We found that a clinically applicable Akt/p70S6K dual inhibitor, LY2780301, drastically decreased proliferation of hMECs with ErbB2-induced p70S6K activation via Cyclin B1 inhibition and cell-cycle blockade at G0–G1 phase, while it did not significantly reverse the abnormal acinar morphology of these hMECs. In addition, a brief treatment of LY2780301 in MMTV-neu mice that developed atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions with activated p70S6K was sufficient to suppress S6 phosphorylation and decrease cell proliferation in hyperplasic MECs. In summary, targeting the aberrant Akt/p70S6K activation in ER− hMEC models in vitro and in the MMTV-neu transgenic mouse model in vivo effectively inhibited Akt/S6K signaling and reduced proliferation of hMECs in vitro and ADH/MIN lesions in vivo, indicating its potential in prevention of p70S6K activated ER− breast cancer. Cancer Prev Res; 10(11); 641–50. ©2017 AACR.

项与 LY-2780301 相关的新闻（医药）

2024-06-20

·药时代

AKT抑制剂，再传噩耗！

失败的III期临床试验 2024年6月18日，阿斯利康公布了一项III期临床的失败。阿斯利康公布CAPItello-290研究最新进展（图源：阿斯利康官网）该试验名为CAPItello-290，是一项随机双盲III期试验，共纳入患者923人，旨在评估其AKT抑制剂Capivasertib（商品名：Truqap）联合化疗（紫杉醇）作为局部晚期（无法手术）或转移性三阴乳腺癌（TNBC）患者一线治疗的疗效与安全性。试验主要终点包括：（1）总体试验人群的OS（2）携带特定生物标志物改变（PIK3CA、AKT1或PTEN）亚组的OS。试验结果显示，Truqap联用组合并未达总生存期改善（OS）双重主要终点，即无论是试验总人群，还是生物标志物亚组人群均未发现OS显著改善。此外，安全性方面与既往研究一致，未发现新的安全性问题。目前，阿斯利康尚未披露该试验详细临床数据，具体公布时间未定。阿斯利康的多重保险 Truqap是一款“First-in-class”AKT抑制剂，可选择性靶向3种AKT激酶异形体AKT1/2/3的腺苷三磷酸（ATP）。该药物首次获批于2023年11月，被FDA批准用于与氟维司群联用治疗HR+/HER2-的晚期或转移性乳腺癌成年患者。虽然Truqap上市时间较短，但在2023年第一季度（即第一个完整收益期），该药物却实现了5000万美元的销售额。有海外分析师认为，Truqap的峰值销售额可达38亿美元。因此阿斯利康对Truqap十分重视，除了TNBC的适应症拓展，公司还相继开展了一项用于三联疗法的III期研究（Truqap+CDK4/6+氟维司群一线治疗HR+/HER2-晚期乳腺癌）; 两项关于前列腺癌的III期研究（Truqap+多西他赛治疗mCRPC；Truqap+阿比特龙治疗PTEN缺失的mhspc）。其中，关于Truqap与阿比特龙的联用数据（CAPItello-281研究）将于今年下半年读出。多歧路，今安在迄今为止，在HR+/HER2-乳腺癌一线治疗药物中，CDK4/6抑制剂可谓占据“半壁江山”；在前列腺癌治疗药物中，AR拮抗剂、CYP17抑制剂也均牢牢把握一线治疗市场。而AKT作为PI3K/AKT/m-TOR信号级联的中心节点，在调节细胞存活、增殖、迁移和分化等多种细胞功能中发挥着关键作用。且目前AKT已被证明可以作为多种疾病的治疗靶点，如乳腺癌、前列腺癌、卵巢癌等。 Truqap便是个极好的例子，有望横跨乳腺癌与前列腺癌两大适应症，潜力不可谓不大。然而这样的“宝藏分子”，研发格局却并算不上拥挤，上市产品仅有Truqap一款。根据智慧芽数据统计，目前进入三期临床的AKT抑制剂也仅只有6款。进入三期临床的AKT抑制剂（图片来源：智慧芽数据库）为何？因为在此之前，最早介入探索的公司和产品，如礼来的LY2780301、拜耳的BAY1125976、默沙东的MK-2206等均以失败告终，使得AKT赛道遇冷。 2023年2月，罗氏的AKT抑制剂ipatasertib虽在3期IPATential150研究中观察到了中位PFS改善。但rPFS获益一般，且未证明OS改善。加上此次Truqap又在TNBC适应症上失利，使得该赛道再次蒙上阴影。 AKT抑制剂的作用机制非常复杂，且具有多靶点抑制、缺乏精准选择、生物利用度低、严重的不良反应等多重挑战，等待研发人员攻克。如何探索更合适的给药间隔和频次，如何进一步提升药物效能，便成为了后继者们实现弯道超车的关键所在。回顾国内，来凯医药、海昶生物、正大天晴等药企有所布局，且来凯医药的afuresertib处在临床三期阶段。参考资料：阿斯利康官网智慧芽数据库 NMPA全球首批AKT靶点药物上市！乳腺癌患者治疗迎来新曙光（）（梅斯肿瘤新前沿）横跨两大难病的下一个国产重磅炸弹（瞪羚社）全球首款！阿斯利康Capivasertib申报上市，浅谈AKT抑制剂研发进展（药渡）其他公开资料封面图来源：pixabay 版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 止步II期临床？命途多舛的 “Wee 1” 股价暴涨477%，CD20 CAR-T再突破 >50%破发！2024年纳斯达克IPO的biotech公司依然面临挑战点击这里，发现价值信息！

临床3期临床失败申请上市

2023-11-13

·SYNAPSE

What are Akt inhibitor and how do you quickly get the latest development progress?

Akt, also known as protein kinase B, is a crucial enzyme that plays a significant role in various cellular processes within the human body. It is a key mediator of cell survival, growth, and metabolism. Akt is involved in regulating multiple signaling pathways, including those related to cell proliferation, apoptosis, and glucose metabolism. It promotes cell survival by inhibiting apoptosis and stimulating cell growth and proliferation. Akt also regulates glucose metabolism by promoting glucose uptake and utilization. Dysregulation of Akt signaling has been implicated in various diseases, including cancer, diabetes, and neurodegenerative disorders. Understanding the role of Akt is essential for developing targeted therapies in the pharmaceutical industry. Basic research related to AKT has a relatively high academic starting point, with the earliest literature recorded in the top-tier journal "Proceedings of the National Academy of Sciences (PANS)". The prototype AKT gene was published in the journal Science in 1991. Due to the solid academic foundation established at the beginning, AKT has garnered attention in drug development from many pharmaceutical giants. Reviewing the development history of AKT drugs, the earliest companies involved in the exploration and clinical development of AKT inhibitors were pharmaceutical giants such as GlaxoSmithKline, Merck, Eli Lilly, Bayer, AstraZeneca, and Roche (Genentech). However, despite their well-known backgrounds, these companies have either sold off or terminated their AKT inhibitor developments, such as Eli Lilly's LY2780301 and Bayer's BAY1125976. This to some extent reflects the uncertainty of new drug development as well as the enormous complexity and challenges of the AKT signalling pathway. Merck's MK-2206 also ultimately failed after more than 40 early trials. Inherent or acquired drug resistance has always been the main reason why cancer drugs cannot maintain effectiveness, and eventually leads to treatment failure. Therefore, with the continuous exploration of potential mechanisms, discovering more promising drug targets has become the optimal treatment method for cancer treatment and prevention. The aberrant activation of the PI3K/AKT pathway and the transduction of its upstream or downstream targets play a crucial role as an important signalling pathway responsible for the resistance formation of various tumours. To enhance the sensitivity of tumour cells and combat tumour drug resistance, AKT inhibitors have also made some progress in clinical research. For example, in breast cancer, the PI3K/AKT pathway is considered a key player in the development of endocrine therapy resistance. The combined use of AKT inhibitors counteracts the activation of the PI3K/AKT pathway, thus exerting cytotoxic activity to prevent tumour cell resistance. Therefore, AstraZeneca and Roche are also evaluating the use of AKT inhibitors alone or in combination to develop new therapies for tumour treatment and to address treatment resistance. How do they work?AKT inhibitors are a type of medication that target and inhibit the activity of the AKT The AKT , also known as protein kinase B, plays a crucial role in cell survival, growth, and proliferation. It is involved in various signaling pathways that regulate cell processes such as metabolism, apoptosis (cell death), and cell cycle progression. In the context of biomedicine, AKT inhibitors are of particular interest in cancer research and treatment. Dysregulation or overactivation of the AKT is commonly observed in many types of cancer, leading to uncontrolled cell growth and survival. By inhibiting the activity of the AKT , these inhibitors aim to disrupt the signaling pathways that promote cancer cell growth and induce cell death. AKT inhibitors can be developed as small molecules or targeted therapies, such as monoclonal antibodies or kinase inhibitors. They work by binding to specific regions of the AKT protein, preventing its activation or downstream signaling cascades. These inhibitors have shown promise in preclinical and clinical studies as potential anticancer agents, either as standalone treatments or in combination with other therapies. It is important to note that the use of AKT inhibitors may have potential side effects and limitations. Since AKT is involved in various cellular processes, inhibiting its activity can affect normal cell functions as well. Therefore, careful evaluation of the therapeutic benefits and risks is necessary when considering the use of AKT inhibitors in clinical settings. List of Akt InhibitorsThe currently marketed Akt inhibitors include: CapivasertibAfuresertibDordaviproneHonokiolIpatasertib DihydrochloridePerifosineSR-0379AntroquinonolCLR-131HC0201For more information, please click on the image below. What are Akt inhibitors used for?Akt inhibitors are being studied for the treatment of multiple diseases, including ovarian, prostate, breast, gastric, multiple myeloma, and melanoma. For more information, please click on the image below to log in and search. How to obtain the latest development progress of Akt inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of Akt inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

2022-11-02

·研发客

capivasertib三期成功，AKT赛道AZ罗氏来凯三头并进 | 研究院

近日，阿斯利康宣布其AKT抑制剂capivasertib的Ⅲ期临床研究CAPItello-291的结果：与氟维司群单药相比，capivasertib联用氟维司群能显著改善晚期HR+乳腺癌患者的无进展生存期（PFS），达到了主要研究终点。阿斯利康还表示，AKT抑制剂可能成为HR+乳腺癌内分泌治疗耐药的新选择。AKT即丝氨酸/苏氨酸蛋白激酶（serine/threonine kinase），在细胞生长和增殖、凋亡抑制和血管生成的传导机制中发挥关键作用，是PI3K/AKT/mTOR信号通路的关键分子。目前全球尚无AKT抑制剂上市，仅有3款产品进入关键临床研究阶段（含临床III期及注册临床II期）：除已获得积极数据的capivasertib，还有罗氏的ipatasertib（GDC-0068），以及本土“黑马”来凯医药的afuresertib（LAE002）。这三款产品构成全球AKT研发的第一梯队，谁有机会率先终点冲线，且拭目以待。HR+乳腺癌耐药新策略HR+（激素受体阳性）/ HER2-（人表皮生长因子受体2阴性）是乳腺癌的最常见亚型，约占乳腺癌患者总数的70%。各国指南推荐该类患者的治疗方案包括内分泌疗法和CDK4/6抑制剂，而许多晚期乳腺癌患者在治疗后会产生耐药性，治疗选择有限。阿斯利康的capivasertib在HR+/HER2-乳腺癌领域，瞄准的是经内分泌疗法和CDK4/6抑制剂治疗耐药后的患者群体。Ⅲ期临床试验CAPItello-291招募的全部为接受内分泌联合或不联合CDK4/6抑制剂治疗期间或之后发生疾病复发或进展的乳腺癌患者，其中约40%的患者发生PIK3CA/AKT1/PTEN突变。该试验共纳入708例患者，评估capivasertib联合氟维司群对比安慰剂联用氟维司群治疗HR+/HER2-乳腺癌患者的疗效和安全性。结果显示，在主要疗效终点——总体人群和携带PIK3CA/AKT1/PTEN基因突变患者亚组的无进展生存期中，capivasertib联合氟维司群组都达到了疗效终点，PFS均具有统计学意义和临床意义的改善。次要终点总生存期（OS）数据尚不成熟。阿斯利康的成功无疑给整个AKT抑制剂研发领域增加了信心。国内企业来凯医药也布局了HR+/HER2-乳腺癌的开发。其核心产品afuresertib联合氟维司群治疗HR+/HER2-乳腺癌的全球多中心Ⅰb/Ⅲ期临床研究已经启动，今年5月，来凯宣布该临床研究完成受试者入组及首例给药。2018年，来凯从诺华引进afuresertib，获得该药的全球独家开发、生产及商业化权益。在国内，其他正在开发的AKT产品还有正大天晴的NTQ1062、海昶生物的WGI-0301，这两款产品正在开展治疗实体瘤的Ⅰ期临床。珍宝岛药业的HZB0071和浙江大学的Hu7691分别在2018年和2020年获得IND批准，但后续未见有进一步临床进展。多类肿瘤耐药性与AKT过表达相关除了HR+/HER2-乳腺癌，研发客还观察到AKT抑制剂在多个肿瘤领域均有临床研究开展。这与AKT靶点机制有很大关系。研究显示，卵巢癌、前列腺癌、乳腺癌等肿瘤的耐药性与AKT的过度表达高度相关。约40%的卵巢癌和乳腺癌，以及超过50%的前列腺癌中，均表现出AKT1激酶活性增加；近80%的激活AKT1的肿瘤为高分级和Ⅲ/Ⅳ期癌。约40%的卵巢癌中表现出AKT2激酶的活性。在雌激素受体缺陷型乳腺癌和雄激素不敏感的前列腺癌细胞系中，AKT3活性升高。来凯医药选择卵巢癌作为afuresertib的首个开发适应症，正在开展afuresertib联合紫杉醇针对铂耐药卵巢癌的全球多中心Ⅱ期注册临床研究（PROFECTA-Ⅱ）。目前卵巢癌的治疗手段主要是铂类为基础的化疗联合或不联合贝伐珠单抗或PARP抑制剂，但仍有超过80%患者的初始治疗后复发并产生耐药性，耐药后治疗方案有限。第一次复发患者中约25%为铂耐药性复发性卵巢癌（PROC），几乎所有复发性卵巢癌（ROC）患者最终都会产生铂耐药。根据先前诺华公开的数据，afuresertib已在临床前研究中证实其在PROC细胞系中恢复铂/紫杉醇敏感性的能力。已完成的Ⅰb期研究中，afuresertib在PROC患者中显示出潜在的抗肿瘤疗效，总缓解率（ORR）为32%，无进展生存期（PFS）达到7.1个月。在前列腺癌这一适应症上，阿斯利康、罗氏、来凯医药这三家公司都有布局。阿斯利康发起的一项Ⅱ期治疗转移性去势抵抗性前列腺癌（mCRPC）的临床试验ProCAID表明，capivasertib联合化疗治疗组的中位总生存期明显长于化疗对照组（31.2个月对照20.3个月）。来凯医药则将afuresertib与CYP17A1/CYP11B2双靶点抑制剂LAE001联用，探索对前列腺癌患者的二至四线治疗潜力，正在Ⅱ期研究中。罗氏的IPATunity150试验也取得部分成功，在携带PTEN缺失的mCRPC患者中，ipatasertib联合阿比特龙和泼尼松相比安慰剂组，能显著提高患者的放射学无进展生存期（rPFS）。但在总体人群中，ipatasertib未达到研究终点。除了肿瘤适应症，还有部分公司探索到了罕见病和皮肤疾病领域。例如Vaderis Therapeutics开发的VAD044，正在开展遗传性出血性毛细血管扩张症（HHT）的Ⅰ期临床研究。有研究发现，在HHT模型中过度激活PI3K-AKT信号通路，可以抑制血管过度扩张，减少动静脉畸形（AVM）形成，以缓解HHT的症状。DermBiont公司还开发了一款AKT外用制剂SM-020，治疗脂溢性角化病，处于Ⅱ期临床研究中。失败中探索AKT抑制剂的研发之路并非一帆风顺。比如，默沙东的MK-2206、礼来的LY2780301即折戟在研发早期阶段。罗氏的ipatasertib的两项乳腺癌Ⅲ期临床试验Ipatunity-130和Ipatunity-170在2021年相继终止。其中，Ipatunity-130是评估ipatasertib联合紫杉醇一线治疗PIK3CA/AKT1/PTEN突变TNBC或HR+/HER2-乳腺癌的疗效和安全性的研究，Ipatunity-170是ipatasertib联合阿替利珠单抗和紫杉醇一线治疗晚期三阴性乳腺癌（TNBC）的研究。研发客研究院观察到一个有趣的现象，虽然罗氏两项试验均在一线治疗上失败，但阿斯利康CAPItello-291研究瞄准的是现有治疗手段耐药后的二线患者群体，招募患者中约40%存在PIK3CA/AKT1/PTEN突变，来凯afuresertib对标的也是现有标准治疗耐药的患者。这不由得让人猜想：耐药后AKT过表达或许才是开启该领域的“钥匙”。不过，新药研发之路变幻莫测，阿斯利康CAPItello-291研究的成功是否与肿瘤耐药后AKT的过度表达有关，还有待更多的临床研究和试验数据去证实。总第1745期访问研发客网站可浏览更多文章www.PharmaDJ.com

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100 项与 LY-2780301 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
局部晚期乳腺癌	临床2期	法国	Institut Jean Paoli & Irene Calmettes	2014-01-01
转移性乳腺癌	临床2期	法国	Institut Jean Paoli & Irene Calmettes	2014-01-01
非霍奇金淋巴瘤	临床1期	法国	Gustave Roussy, Cancer Campus, Grand Paris	2013-09-01
实体瘤	临床1期	法国	Gustave Roussy, Cancer Campus, Grand Paris	2013-09-01
肿瘤转移	临床1期	西班牙	Eli Lilly & Co.	2010-03-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01980277 (TAKTIC, Pubmed \| Eur J Cancer)	临床2期	HER2 阴性乳腺癌 HER2-negative \| PI3K/AKT pathway	51	LY2780301 500 mg QD+ paclitaxel 80 mg/m2	齋蓋醖膚鑰構簾獵壓構(淵憲網範獵構醖廠衊衊) = 襯鏇襯網選範觸醖鑰壓蓋齋積窪淵憲觸廠鹹願 (選鹹憲鑰鹽糧憲網鑰積, 48.8 ~ 76.8)	-	2021-12-01
NCT01980277 (TAKTIC, ASCO2019)	临床2期	HER2 阴性乳腺癌	35	LY2780301 + wP	廠獵網網繭夢遞糧簾鏇(衊製鑰鬱鬱網鹽衊鏇艱) = 50% of pts, G3-4 in 8% 糧鑰選憲築憲憲壓夢築 (衊淵窪夢膚廠獵艱膚構 ) 更多	积极	2019-05-26
NCT02018874 (INPAKT, Pubmed \| Eur J Cancer) 人工标引	临床1期	肿瘤	50	LY2780301+gemcitabine	鹹齋糧膚夢製淵膚鹹壓(築鬱衊廠範繭遞範顧鏇) = anaemia (84%), fatigue (84%), transaminase increase (74%), thrombocytopenia (74%), nausea/vomiting (70%), neutropenia (68%) and lymphopenia (56%) 夢齋繭願範廠鹹艱構壓 (齋艱顧鬱齋顧鹽憲鬱製 ) 更多	积极	2017-09-01
NCT01115751 (Pubmed \| Invest New Drugs) 人工标引	临床1期	肿瘤转移	32	LY2780301	壓願願繭蓋製艱構餘鏇(壓範艱憲願構醖製淵範) = 壓膚願鹹網餘構遞齋餘齋積淵餘選鏇築願襯廠 (鑰醖艱簾餘窪衊構蓋網 ) 更多	积极	2015-06-01
ASCO2012	临床1期	实体瘤	32	LY2780301	憲構齋繭夢壓膚獵鹹衊(襯願窪淵範簾鏇觸鑰衊) = prolonged stable disease for 6.5 cycles 觸醖壓齋構衊獵遞憲鹹 (選構醖襯繭鬱選餘網蓋 ) 更多	-	2012-05-20