Phase 2 Study of Paclitaxel (NSC #673089) + Ipatasertib (NSC #781451) in Taxane-Refractory Participants With AKT-Altered Advanced Non-Breast Solid Tumors: A ComboMATCH Treatment Trial

This phase II ComboMATCH treatment trial tests the usual treatment of chemotherapy (paclitaxel) plus ipatasertib in patients with solid tumor cancers that that cannot be removed by surgery (unresectable), has spread to nearby tissue or lymph nodes (locally advanced) or from where it first started (primary site) to other places in the body (metastatic), and has an AKT genetic change. Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Targeted therapy, such as Ipatasertib, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The addition of ipatasertib to paclitaxel in solid tumors with an AKT genetic change could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression). Researchers hope to learn if paclitaxel plus ipatasertib will shrink this type of cancer or stop its growth.

开始日期2023-09-22

申办/合作机构

National Cancer Institute

NCT05332561 / Recruiting临床2期

Genomics Guided Targeted Post-neoadjuvant Therapy in Patients With Early Breast Cancer - a Multicenter, Open-label, Umbrella Phase-II Study - COGNITION-GUIDE

In early breast cancer (eBC), pathological complete response (pCR) after neoadjuvant therapy acts as surrogate marker for metastasis and overall survival. Therapy intensification by adding an adjuvant therapy line (post-neoadjuvant treatment) substantially lowers the risk of relapse in high-risk breast cancer patients with residual disease after neoadjuvant treatment (non-pCR). While this approach was exemplified in two phase III trials without biomarker-stratification (CREATE-X, KATHERINE), even higher efficiency might be achieved by individualized genomic-guided post-neoadjuvant therapies.
Within the seven-arm umbrella phase-II clinical trial COGNITION-GUIDE, we aim to deliver molecularly-tailored cancer care by implementing an additional response- and genomics-guided post-neoadjuvant therapy after finishing the guideline-compliant post-neoadjuvant treatment in high-risk breast cancer patients with residual cancer burden after neoadjuvant therapy to reduce the substantial risk of local and distant relapse.
The trial evaluates not a single drug but rather a general strategy of precision oncology in the curative setting and provides the basis for future confirmatory biomarker-driven trials.
Allocation to the therapy-arms is conducted by in depth molecular characterization of tumors within the COGNITION registry program.
The study aims to show an overall benefit of the precision medicine approach in high-risk eBC patients and to allow for secondary exploratory evaluation of each study-arm.
The primary endpoint of the study is invasive Disease-Free Survival (IDFS) after 4 years measured from surgery to local or distant relapse or death. The sample size of the entire trial is 240 eligible patients.

开始日期2023-06-29

申办/合作机构

German Cancer Research Center

NCT05862285 / Recruiting临床3期

An Open-Label, Multicenter Extension Study in Patients Previously Enrolled in a Genentech and/or F. Hoffmann-La Roche Ltd Sponsored Study

The purpose of this extension study is to provide continued treatment with Roche investigational medicinal product (IMP[s]) monotherapy or Roche IMP(s) combined with other agent(s) or comparator agent(s) for eligible participants with cancer who are still on study treatment at the time of roll-over from the parent study and who do not have access to the study treatment locally.

开始日期2023-06-01

申办/合作机构

F. Hoffmann-La Roche Ltd.

100 项与 Ipatasertib Dihydrochloride 相关的临床结果

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100 项与 Ipatasertib Dihydrochloride 相关的转化医学

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100 项与 Ipatasertib Dihydrochloride 相关的专利（医药）

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109

项与 Ipatasertib Dihydrochloride 相关的文献（医药）

2024-02-16·Clinical cancer research : an official journal of the American Association for Cancer Research

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results

Article

作者: Chae, Yeesoo ; Huang, Xiayu ; Lee, Jieun ; Dent, Rebecca ; Barrios, Carlos H. ; Saji, Shigehira ; Turner, Nicholas C. ; Jones, Surai ; Freitas-Junior, Ruffo ; Espinosa, Enrique ; Oliveira, Mafalda ; Reilly, Sarah-Jayne ; Sablin, Marie-Paule ; Shah, Kalpit ; Italiano, Antoine ; Boni, Valentina ; Vidal, Gregory A. ; Martinez Rodriguez, Jorge Luis ; Kim, Sung-Bae ; White, Shane ; Torres Mattos, Cesar ; Bondarenko, Igor ; Savas, Peter ; Lam, Lisa H. ; O'Shaughnessy, Joyce ; Schmid, Peter ; Rojas, Beatriz ; Isakoff, Steven J.

Abstract:

Purpose::

To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC).

Patients and Methods::

The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1–21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance.

Results::

Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels.

Conclusions::

In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.

2023-12-12·Annals of medicine

Ipatasertib, an oral AKT inhibitor, in combination with carboplatin exhibits anti-proliferative effects in uterine serous carcinoma

Article

作者: Deng, Boer ; Newton, Meredith A. ; Zhao, Ziyi ; Sun, Wenchuan ; Bae-Jump, Victoria ; Zhou, Chunxiao ; Secord, Angeles Alvarez ; Burkett, Wesley C.

PURPOSE:

Uterine serous carcinoma (USC) exhibits worse survival rates compared to the endometrioid subtype, and there is currently no effective treatment options for recurrence of this disease after platinum-based chemotherapy. Activation of PIK3CA/AKT/mTOR signaling pathway is a common biological feature in USC.

MATERIALS AND METHODS:

Ipatasertib (IPAT) is an investigational, orally administered, ATP-competitive, highly selective inhibitor of pan AKT that has demonstrated anti-proliferative activity in a variety of tumor cells and tumor models. In this study, we used IPAT, carboplatin and their combination to investigate the anti-tumor activity in SPEC-2 and ARK-1 cells.

RESULTS:

Our results indicate that IPAT combined with carboplatin at low doses was more effective at reducing proliferation, inducing apoptosis and causing cellular stress than IPAT or carboplatin alone. In particular, inhibition of the PIK3CA/AKT/mTOR pathway and induction of DNA damage were involved in the synergistic inhibition by combination treatment of cell viability in USC cells treated with the combination. Furthermore, IPAT in combination with carboplatin significantly reduced cell adhesion and inhibited cell invasion.

CONCLUSIONS:

These findings suggest that the combination of IPAT and carboplatin has potential clinical implications for developing new USC treatment strategies.

2023-10-01·Drug metabolism and disposition: the biological fate of chemicals

The Absolute Bioavailability and Absorption, Metabolism, and Excretion of Ipatasertib, a Potent and Highly Selective Protein Kinase B (Akt) Inhibitor.

Article

作者: Kshirsagar, Smita ; Musib, Luna ; Sane, Rucha ; Malhi, Vikram ; Deng, Yuzhong ; Ma, Shuguang ; Dean, Brian ; Cho, Sungjoon ; Liederer, Bianca M ; Al-Sayah, Mohammad A ; Nugteren, James ; Takahashi, Ryan H ; Yost, Edward

Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using ¹⁴C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (period 1) and mass balance and metabolite profiling (period 2). In period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by an 80 μg (800 nCi) intravenous dose of [¹⁴C]-ipatasertib. In period 2, subjects received a single oral dose containing approximately 200 mg (100 μCi) [¹⁴C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the ¹⁴C microtracer intravenous pharmacokinetics in period 1 and fully profile plasma radioactivity in period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives after oral and intravenous administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. After a single oral dose of [¹⁴C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating that ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was N-dealkylation mediated by CYP3A, and minor pathways were oxidative by cytochromes P450 and aldehyde oxidase. SIGNIFICANCE STATEMENT: The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small-molecule inhibitor of protein kinase B (Akt). An ultrasensitive radioactive counting method, accelerator mass spectrometry was successfully applied for ¹⁴C-microtracer absolute bioavailability determination and plasma metabolite profiling.

项与 Ipatasertib Dihydrochloride 相关的新闻（医药）

2024-06-02

·PRNewswire

MEDSIR's PRIMED Study Shows Promising Results for Preventing Sacituzumab Govitecan related Side Effects in the Treatment of HER2-negative Advanced Breast Cancer

The PRIMED study found a way to reduce treatment-related side effects among participants, decreasing dose reductions, treatment interruptions, and permanent discontinuations. The strategic alliance between MEDSIR and Oncoclínicas has enabled the company to present 13 studies at the 2024 ASCO Annual Meeting. CHICAGO, June 2, 2024 /PRNewswire/ -- Leading international medical research company, MEDSIR, today announced the results of the recent PRIMED clinical trial during the 2024 ASCO Annual Meeting. Carried out under the company's collaborative model, this Investigator-Initiated Trial (IIT) demonstrated the effectiveness of preventative administration of drugs to treat the common side effects of neutropenia and diarrhea that can occur while taking sacituzumab govitecan, an antibody-drug conjugate targeting Trop-2 that has extended overall survival for patients with pretreated triple negative and HR-positive/HER2-negative advanced breast cancer in two previous Phase 3 studies, ASCENT and TROPiCS-02. In the PRIMED study, adding primary prophylactic granulocyte colony-stimulating growth factors (G-CSF) and loperamide during the first two sacituzumab govitecan treatment cycles led to clinically meaningful reductions in neutropenia and diarrhea, lowering the need for dose reductions, treatment interruptions, and permanent discontinuations. Continue Reading Dr. Antonio Llombart-Cussac and Dr. Javier Cortés at ASCO24 Dr. Antonio Llombart-Cussac and Dr. Javier Cortés at ASCO "This is an exciting finding that highlights the high potential of prophylactic strategies that can mitigate side effects to help keep patients on promising treatments, which was made possible by our collaborative research model," shared Dr. Antonio Llombart-Cussac, Senior Scientific Leader of MEDSIR. "By using a partnership model that combines the benefits of company-sponsored research with all the advantages of IITs, we are turning brilliant ideas into full clinical trials that will safely and efficiently advance cancer solutions. It is our hope that, by working together, we will continue to generate new opportunities for patients worldwide." Among PRIMED study participants, the incidence of any grade of neutropenia (in the first two cycles) was 28%, compared to 63% and 70% in ASCENT and TROPiCS-02 (in the full study), respectively. The incidence of any grade diarrhea (in the first two cycles) was 34%, compared to 59% and 57% in ASCENT and TROPiCS-02 (in the full study), respectively. The other side effects PRIMED study participants experienced were consistent to the known safety profile of sacituzumab govitecan, with the exception of constipation, which occurred in 46% of patients during the first two cycles compared to 17% in ASCENT and 19% in TROPiC-02 (in the full study). However, most cases of constipation were mild, and no patients experienced adverse events that led to permanent treatment discontinuation. The study, which is still ongoing to evaluate efficacy and collect longer-term safety data, enrolled 50 patients between February 2023 and September 2023 across 10 sites across Spain, providing them with G-CSF and loperamide during the first two sacituzumab govitecan treatment cycles (physician's decision to continue after two cycles). These two drugs are commonly used to treat neutropenia and diarrhea, respectively, but are usually administered only after these side effects occur. In PRIMED, researchers wanted to test whether early administration of these drugs, before patients experienced any neutropenia or diarrhea, could reduce the incidence of these side effects and determine how this affected the need for dose reductions, treatment interruptions, and permanent discontinuations. Showcasing Numerous Promising Collaborative Trials at ASCO PRIMED was not the only trial MEDSIR presented during the ASCO Annual Meeting. It shared the results of several other recent and ongoing studies as well. Recently published in The Lancet, MEDSIR's PHERGain phase II trial (NCT03161353) demonstrated how a third of patients with HER2-positive early breast cancer could be safely treated without using chemotherapy. At the 2024 ASCO Annual Meeting, MEDSIR presented a subanalysis of this study comparing PET scan and magnetic resonance imaging (MRI) results; both tests that participants undergo to observe the evolution of their cancer. The comparative study shows tumor assessments can be analyzed with both PET scan and MRI. Although PET scan is the recommended imaging technique for early treatment response, this exploratory study suggests that MRI could alternatively guide the treatment when PET scan are not available. MEDSIR's PATHFINDER study evaluated the safety, tolerability, and preliminary efficacy of ipatasertib in combination with non-taxane chemotherapy in patients with advanced triple negative breast cancer who had previously experienced tumor progression after treatment with taxane chemotherapy. Study results revealed that combining ipatasertib with capecitabine and eribulin has an acceptable safety profile in these patients, but that adding ipatasertib alongside carboplatin plus gemcitabine proved to be intolerable. Additionally, the combination of ipatasertib and eribulin demonstrated encouraging efficacy, warranting further investigation. TUXEDO-3, one of MEDSIR's ongoing clinical trials in Austria and Spain, is the first study evaluating the efficacy and safety of patritumab deruxtecan as an anti-cancer therapy for patients with pretreated metastatic breast cancer and advanced non-small cell lung cancer with brain metastases, and metastatic solid tumors with leptomeningeal disease. If positive, this study could streamline the introduction of HER3-DXd as a new treatment for these patients who currently have very limited therapeutic options. ABOUT UMMET CANCER NEEDS Unmet cancer needs refer to gaps in resources, support, and treatment options that exist for cancer patients. Addressing unmet cancer needs is crucial to improving quality of life and outcomes for cancer patients. Through the collaborative work of healthcare providers, policymakers, and patient advocacy groups unmet cancer needs can be identified to help provide patients with comprehensive and quality care. ABOUT MEDSIR Founded in 2012, MEDSIR works closely with its partners to drive innovation in oncology research. Based in Spain and the United States, the company manages all aspects of clinical trials, from study design to publication, utilizing a global network of experts and integrated technology to streamline the process. The company offers proof-of-concept support and a strategic approach that helps research partners experience the best of both worlds from industry-based clinical research and investigator-driven trials. To promote independent cancer research worldwide, MEDSIR has a strategic alliance with Oncoclínicas, the leading oncology group in Brazil with the greatest research potential in South America. Learn how MEDSIR brings ideas to life at . SOURCE MEDSIR

临床结果ASCO会议临床2期临床3期

2024-05-23

·PRNewswire

Rutgers Cancer Institute and RWJBarnabas Health Set to Unveil Extensive, New Cancer Research Findings at 2024 ASCO Annual Meeting

49 scheduled presentations will explore several types of cancer, as well as the next frontier of health equity NEW BRUNSWICK, N.J., May 23, 2024 /PRNewswire/ -- Clinicians and scientists from Rutgers Cancer Institute and RWJBarnabas Health will lead sessions and present their latest discoveries from their innovative cancer research program at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, to be held in Chicago (and online) from May 30-June 4. A total of 49 accepted abstracts and presentations will cover cutting-edge topics, including two oral sessions highlighting the National Surgical Quality Improvement Program (NSQIP) audit of enhanced recovery after surgery protocols for radical cystectomy, as well as social vulnerability and clinical trial enrollment's role in the next frontier of health equity. Continue Reading Rutgers Cancer Institute and RWJBarnabas Health "Our world-renowned integrated network of researchers and clinicians at Rutgers Cancer Institute and RWJBarnabas Health continues to innovate and investigate strategies that will achieve the best possible outcomes for our patients. This is reflected in the dynamic lineup of presentations featured at the 2024 ASCO Annual Meeting, underscoring our team's commitment and dedication," said Steven K. Libutti, MD, FACS, Director, Rutgers Cancer Institute and Senior Vice President, Oncology Services, RWJBarnabas Health. "As New Jersey's only National Cancer Institute-designated Comprehensive Cancer Center and the leading cancer program in the state, we are at the forefront of advancing cancer research and care to conquer a disease that impacts so many. We look forward to sharing our array of recent advancements and findings at this year's meeting." The research accepted for presentation at ASCO includes one late-breaking abstract, oral and poster sessions as well as publication-only abstracts highlighting data in numerous types of cancer, including breast, colorectal, lymphoma, and lung. Highlights of the accepted abstracts include the following: Findings from a study that assesses how social vulnerability impacts clinical trial enrollment and explores the interaction between race and social vulnerability among patients with one of the top five cancers - breast, prostate, lung, colorectal and pancreas. Findings confirm that neighborhood social vulnerability is a barrier to trial enrollment, even more so among Black patients. Utilization of enhanced recovery after surgery (ERAS) protocols for radical cystectomy has been associated with improved postoperative recovery and shorter hospital stays. This study was designed to assess the impact of increasing compliance to ERAS components on postoperative outcomes in patients who underwent radical cystectomy. Researchers reviewed 3,708 patients from the National Surgical Quality Improvement Program database who underwent radical cystectomy from 2019 – 2021. Updates from CTEP 10492, a Phase 1/1b study investigating the AKT inhibitor ipatasertib with chemoradiation to treat locally advanced head and neck squamous cell carcinoma (HNSCC). The primary objective of this study is to determine the maximum tolerated dose and recommended Phase 2 dose of ipatasertib in combination with definitive chemoradiation therapy (CRT) in locally advanced HNSCC based on dose-limiting toxicities. This phase 1/1b study will be the first to establish safety and preliminary efficacy of ipatasertib combined with standard of care definitive CRT for HNSCC. Data from a Phase 3 clinical trial evaluates the efficacy and safety of odronextamab plus CHOP vs rituximab plus CHOP in previously untreated diffuse large B-cell lymphoma (DLBCL) patients. OLYMPIA-3 is a Phase 3, randomized, open-label, multicenter study of O-CHOP vs. R-CHOP in patients with previously untreated DLBCL and intermediate- or high-risk features. The primary endpoints of the study are the incidence of dose-limiting toxicities, and incidence and severity of treatment-emergent adverse events as well as progression-free survival by independent central review. CIPHER (NCT05333874), a single institution pilot study, evaluated whether trend of circulating tumor DNA (ctDNA) testing during neoadjuvant therapy (NAT) can serve as an early indicator of treatment response and inform disease management in the adjuvant setting. The study included 35 patients with stage II-III triple negative and HER2+ breast cancer and longitudinal ctDNA testing performed during standard of care NAT. The full list of presentations at this year's 2024 American Society of Clinical Oncology Annual Meeting can be found here. About Rutgers Cancer Institute As New Jersey's only National Cancer Institute-designated Comprehensive Cancer Center, Rutgers Cancer Institute, together with RWJBarnabas Health, offers the most advanced cancer treatment options, including bone marrow transplantation, proton therapy, CAR T-cell therapy and complex surgical procedures. Along with clinical trials and novel therapeutics such as precision medicine and immunotherapy – many of which are not widely available – patients have access to these cutting-edge therapies at Rutgers Cancer Institute in New Brunswick, Rutgers Cancer Institute at University Hospital in Newark, as well as through RWJBarnabas Health facilities. For journalists – contact: Krista Didzbalis Corporate Communications Specialist, Strategic Communications, RWJBarnabas Health 732.507.8307 [email protected] For patient appointments/inquiries – contact: 844-CANCERNJ (844-226-2376) SOURCE Rutgers Cancer Institute and RWJBarnabas Health

临床3期ASCO会议免疫疗法临床结果细胞疗法

2024-02-29

·同写意

First-in-class的AKT激酶抑制剂capivasertib的药物设计，凭啥杀出重围？

自2016年至今，同写意医药项目合作与交易论坛和估值班已举办多次，被业界誉为国内“医药BD黄埔军校”。应业界人士的要求，今年3月，同写意BD俱乐部将邀请专业导师、实战派总裁就医药BD交易与并购的新逻辑、新策略、新方法进行系统和全面分析与讲解。Akt（也称蛋白激酶B或PKB）是一种丝氨酸苏氨酸激酶，是PI3K-Akt信号通路中的关键节点。该轴是人类癌症中最常失调的信号通路之一，并已被证明可以介导对一系列细胞毒性、抗激素和靶向治疗的耐药性。该通路在细胞生长、增殖、运动和存活中发挥着关键作用，在不同癌症类型中被多种机制激活，包括编码关键成分的基因的体细胞突变、缺失和扩增。Capivasertib是由阿斯利康开发的丝氨酸/苏氨酸激酶AKT（AKT1-3）的ATP竞争性抑制剂，与氟维司群联合用于治疗患有激素受体（HR）阳性、HER2阴性、患有一种或多种PIK3CA/AKT1/PTEN改变的局部晚期或转移性乳腺癌成年患者。1药物设计01从片段到lead首先，通过高通量的分子片段虚拟筛选将氮杂吲哚1鉴定为PKB（即Akt）的ATP竞争性配体。通过与PKB的共晶结构发现杂环N和N−H与激酶的铰链区的Glu121和Val123形成氢键。为了方便合成，用嘌呤代替7-氮杂吲哚，并通过共晶结构启发引入氨基得到6-苯基嘌呤2，碱性氮与酸性残基Glu127和Glu170的主链羰基形成有利的静电相互作用。随后用哌啶取代2中的苯基（便于调整logP和tPSA）并引入4-氨基得到3（碱性胺与Glu和Asn分别形成盐桥和氢键）。图1：从1优化到3的示意图及对应的共晶结构02通过SBDD提高potency为了与P-loop的亲脂口袋相互作用，引入芳香族基团，得到氯苯基取代的分子4。然而，4的高抗增殖活性可能是由于脱靶抑制作用所致，其对10种激酶显示活性，且对PKA激酶没有选择性。神奇的是，当用4-氯苄基替换4-氯苯基，得到的分子5对PKA激酶的选择性提高至约30倍。如图2所示，可能是分子5相对柔性灵活的构象使其在PKB和PKA中采取了不同的结合模式。但5具有高体内清除率和低口服生物利用度，需要进一步优化。03调整pKa/溶解度，提高口服生物利用度尝试了不同位置的SAR，发现通过简单地在5的4-氨基哌啶引入4-酰胺，即可得到PK显著提高的分子6。虽然较低的首过代谢和随后的清除率降低可能有助于提高6的口服生物利用度，但5和6之间的碱性差异也可能发挥一定作用。5和6的pKa（计算）值分别为8.8-9.3和6.5−7.4。预计6在肠道中的质子化程度明显低于5，从而导致被动吸收增强。有趣的是，5的溶解度表现出强烈的pH依赖性，在pH 6.5时S = 0.26 mg/mL，但在pH 7时溶解度可以忽略不计，这表明5的质子化形式的水溶性比非质子化形式大得多。相比之下，6的溶解度受pH值影响较小（pH 7时S = 0.1 mg/mL，pH 6.5时S = 0.04 mg/mL）。因此，非质子化形式更好的溶解度也可能有助于提高6的生物利用度。图2：从分子3优化到6的示意图04提高对ROCK2和hERG的选择性然而，分子6对ROCK2激酶的选择性仅为5倍（ROCK2抑制剂已被证明可显著降低血压并导致心率和心肌收缩力增加），且对hERG的IC50达到5 μM（对hERG的抑制活性与心源性猝死的发生有关）。提高对ROCK2激酶的选择性和降低对hERG的抑制是进一步优化的重点。然而，最初针对hinge区结合基团、酰胺官能团的变化以及伯胺性质和位置的改变都对优化目标没有推进。突破点在于苄基的α-碳取代，首先用碱性侧链取代，发现携带碱性基团的侧链会导致高清除率和低口服生物利用度；随后引入的中性尤其是含羟基（引入羟基是改善hERG抑制活性的常见策略）的侧链则显著提高了对ROCK2和hERG的选择性，最终得到上市药物Capivasertib。图3：从分子6优化到Capivasertib的示意图及对应的共晶结构2市场分析2020年，全球有超过200万患者被诊断患有乳腺癌，近685,000 死亡。HR阳性乳腺癌是最常见的乳腺癌亚型，超过65%的肿瘤是HR阳性且HER2低或阴性。PIK3CA、AKT1和PTEN突变影响高达50%的晚期HR阳性乳腺癌患者。Evaluate Pharma预计Capivasertib的销售峰值约为6.9亿美元。目前有多家药企的AKT抑制剂在II期和III期临床。此前礼来、默沙东和罗氏（Ipatasertib）都在AKT抑制剂上遭遇临床失败。国内药企的话，来凯医药的进度是最快的，目前在二期；其次是恒瑞和正大天晴，目前都在1期。其中，来凯医药的核心管线AKT抑制剂LAE002的前身是2018年从诺华license-in（全球权益）的afuresertib。2024年1月28日，LAE002与紫杉醇联合治疗铂类化疗耐药卵巢癌的二期临床未达到主要临床终点，来凯医药的股价当天暴跌35%。尽管在卵巢癌适应症上失败了，LAE002也在进行和Capivasertib的乳腺癌适应症类似的临床方案，还没到彻底放弃的地步。笔者自觉很难分析为啥那么多MNC都在AKT靶点上失败了，偏偏Capivasertib能杀出重围的背后原因。好几个进入II/III期临床的抑制剂的活性其实都比较接近，分子结构的差异可能是部分原因。另外可能也和阿斯利康保守地选择二线乳腺癌亚型适应症有关，罗氏的Ipatasertib就比较激进地选择了一线治疗的临床方案。AKT抑制剂的案例也充分体现了新药研发的高风险。参考文献：[1] J. Med. Chem. 2013, 56, 5, 2059–2073[2] J. Med. Chem. 2010, 53, 2239–2249[3] J. Med. Chem. 2008, 51, 2147–2157近期直播推荐:

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100 项与 Ipatasertib Dihydrochloride 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	Ipatasertib Dihydrochloride	-	DB11743

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
三阴性乳腺癌	临床3期	美国	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	日本	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	阿根廷	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	澳大利亚	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	奥地利	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	比利时	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	巴西	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	保加利亚	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	加拿大	Hoffmann-La Roche, Inc.	2019-11-25
三阴性乳腺癌	临床3期	哥伦比亚	Hoffmann-La Roche, Inc.	2019-11-25

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临床结果

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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


NCT03498521 (CUPISCO, CTgov)	临床2期	肿瘤	528	platinum (Molecularly-Guided Therapy MGT) Category 1)	膚膚獵繭築範遞醖憲繭(鹹夢構鬱艱糧簾選壓繭) = 選襯範構淵積獵壓網鹽製選窪鏇夢繭廠糧蓋鬱 (襯衊廠獵醖淵網觸壓餘, 夢餘觸構鹹鹽遞糧淵築 ~ 願窪廠選衊簾廠鹽憲顧) 更多	-	2024-06-14
				platinum (Chemotherapy Category 1)	膚膚獵繭築範遞醖憲繭(鹹夢構鬱艱糧簾選壓繭) = 構遞餘簾憲顧築窪蓋範製選窪鏇夢繭廠糧蓋鬱 (襯衊廠獵醖淵網觸壓餘, 獵襯夢淵淵範艱願窪積 ~ 廠鏇構蓋蓋襯願壓鏇鹽) 更多
NCT04589845 (TAPISTRY, ASCO2024)	临床2期	实体瘤	50	Ipatasertib 400 mg	鹽構衊醖製範膚鏇簾蓋(選繭窪襯繭範鹽窪繭鹽) = 壓夢製窪遞積憲觸艱蓋簾餘廠繭壓築繭衊簾壓 (糧鏇觸製鹽簾襯淵獵壓, 18.7 ~ 46.3) 更多	积极	2024-05-24
NCT04464174 (PATHFINDER, ASCO2024)	临床2期	晚期三阴性乳腺癌 PI3K/AKT/mTOR pathway	54	Ipatasertib (IPA) + Capecitabine (CA)	鑰艱淵顧觸獵觸鑰鬱夢(觸願積艱蓋觸餘夢餘壓) = 鑰糧構襯簾鏇簾網願壓願醖鑰淵鬱齋膚積選窪 (鏇觸繭艱觸鹽糧獵簾膚 ) 更多	积极	2024-05-24
				Ipatasertib (IPA) + Eribulin (E)	鑰艱淵顧觸獵觸鑰鬱夢(觸願積艱蓋觸餘夢餘壓) = 壓鏇壓築鏇鑰襯餘網襯願醖鑰淵鬱齋膚積選窪 (鏇觸繭艱觸鹽糧獵簾膚 ) 更多
NCT04177108 (CTgov)	临床3期	三阴性乳腺癌	242	Paclitaxel+Atezolizumab+Ipatasertib (Cohort 1 Arm A: Ipatasertib + Atezolizumab + Paclitaxel)	網餘廠壓糧壓糧窪鬱夢(選齋襯衊鹹壓膚鏇衊選) = 鏇繭衊夢範窪齋鹹構淵夢積顧糧築衊糧餘積餘 (鹽鬱築衊鬱選選獵鏇築, 選齋觸壓窪憲夢夢餘範 ~ 鑰窪窪夢獵鏇選艱夢鏇) 更多	-	2024-03-27
				Paclitaxel+Atezolizumab+Ipatasertib (Cohort 2 Arm A: Ipatasertib + Atezolizumab + Paclitaxel)	網餘廠壓糧壓糧窪鬱夢(選齋襯衊鹹壓膚鏇衊選) = 遞淵願衊選顧獵鏇範衊夢積顧糧築衊糧餘積餘 (鹽鬱築衊鬱選選獵鏇築, 願淵願廠顧膚餘淵觸鏇 ~ 網築襯衊膚鬱憲窪繭鏇) 更多
NCT03337724 (IPATunity130, CTgov)	临床3期	HR阳性/HER2阴性乳腺癌	579	Placebo+Paclitaxel (Cohort A: Placebo + Paclitaxel)	顧製築艱觸遞鏇鏇艱築(襯壓艱獵築選選觸觸鹽) = 齋築簾鬱襯簾淵鹽壓淵糧蓋廠範獵範憲憲鹽遞 (網鬱餘膚鏇鏇廠夢構鹽, 製繭構憲窪鏇憲繭鹹夢 ~ 壓鑰範選範鑰獵醖憲鹽) 更多	-	2024-03-12
				Paclitaxel+Ipatasertib (Cohort A: Ipatasertib + Paclitaxel)	顧製築艱觸遞鏇鏇艱築(襯壓艱獵築選選觸觸鹽) = 鹽構壓鑰壓蓋醖餘艱觸糧蓋廠範獵範憲憲鹽遞 (網鬱餘膚鏇鏇廠夢構鹽, 鹹夢糧範鹽壓糧築窪壓 ~ 醖糧壓膚觸範觸艱願願) 更多
NCT03800836 (CO40151, IPATunity130, IPATunity170, Pubmed)	临床1期	转移性三阴性乳腺癌一线 NF1 \| CCND3 \| PIK3CA ... 更多	317	Ipatasertib 400 mg/day	鑰襯鏇糧顧衊鬱選鑰齋(餘鹽構築願築衊積鬱積) = Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel 襯糧選蓋鏇醖糧鹽淵醖 (遞網壓積繭積網廠蓋獵 )	-	2024-01-09
				Atezolizumab 840 mg
NCT03840200 (CTgov)	临床1期	卵巢癌 \| 乳腺癌 \| 前列腺癌	51	Rucaparib+Ipatasertib (Dose Escalation-Cohort 1)	鹽願鏇糧顧衊顧繭壓衊(網鏇壓築膚鹽構選憲觸) = 製鏇鑰醖齋鑰廠蓋蓋壓艱憲積衊齋選簾鹹醖膚 (製網網製壓襯艱簾鑰鑰, 獵鑰廠壓壓選蓋壓構積 ~ 壓壓獵淵醖積醖鏇蓋艱) 更多	-	2023-10-30
				Rucaparib+Ipatasertib (Dose Escalation-Cohort 2a)	鹽願鏇糧顧衊顧繭壓衊(網鏇壓築膚鹽構選憲觸) = 膚齋醖遞製蓋觸淵餘膚艱憲積衊齋選簾鹹醖膚 (製網網製壓襯艱簾鑰鑰, 鏇糧衊憲鑰艱鬱艱範鑰 ~ 糧憲憲願鏇廠遞膚膚糧) 更多
NCT01485861 (A.MARTIN \| A. MARTIN \| GO27983, CTgov)	临床1/2期	去势抵抗性前列腺癌	298	Prednisone+Abiraterone+Prednisolone+Ipatasertib (Phase II: Ipatasertib 400 mg + Abiraterone)	鏇觸遞選築壓餘顧繭顧(鑰醖鹽齋廠糧簾繭鑰鹽) = 選獵鏇淵製壓鬱糧築網構繭廠獵憲壓鬱積襯構 (糧衊積選鏇獵餘淵獵簾, 餘築選膚壓製襯願獵醖 ~ 鏇鏇襯夢淵網衊選鏇艱) 更多	-	2023-09-14
				Prednisone+Abiraterone+Prednisolone+Ipatasertib (Phase II: Ipatasertib 200 mg + Abiraterone)	鏇觸遞選築壓餘顧繭顧(鑰醖鹽齋廠糧簾繭鑰鹽) = 艱夢蓋築衊窪蓋網遞糧構繭廠獵憲壓鬱積襯構 (糧衊積選鏇獵餘淵獵簾, 淵窪鹽蓋憲膚醖膚齋獵 ~ 範糧簾獵襯窪艱蓋鬱鹹) 更多
NCT03673787 (AACR2023) 人工标引	临床1/2期	胶质母细胞瘤二线 PTEN No Expression	19	Ipatasertib+Atezolizumab	鬱鹽獵夢鏇衊鹽醖鬱窪(鑰壓廠鏇夢築獵鬱鏇鬱) = 積獵遞鹹窪憲蓋積膚蓋選襯製衊繭淵鏇範選築 (壓艱艱遞淵鹽簾顧艱鑰 ) 更多	积极	2023-04-14
				Ipatasertib+Atezolizumab (pts with PTEN loss)	鬱鹽獵夢鏇衊鹽醖鬱窪(鑰壓廠鏇夢築獵鬱鏇鬱) = 簾繭獵範壓範齋壓繭繭選襯製衊繭淵鏇範選築 (壓艱艱遞淵鹽簾顧艱鑰 )
NCT03072238 (IPATential150, CTgov)	临床3期	去势抵抗性前列腺癌 \| 前列腺癌转移	1,101	Placebo+Prednisone/Prednisolone+Abiraterone (Placebo + Abiraterone)	鏇鏇構餘壓範艱廠遞願(膚艱鬱窪遞積顧獵蓋艱) = 積範窪構網構夢簾膚艱鏇遞壓醖遞製壓鹹繭襯 (蓋積鏇廠範簾獵襯構夢, 糧遞製構觸衊願壓糧積 ~ 築蓋築觸夢夢淵選憲壓) 更多	-	2023-04-10
				Prednisone/Prednisolone+Abiraterone+Ipatasertib (Ipatasertib + Abiraterone)	鏇鏇構餘壓範艱廠遞願(膚艱鬱窪遞積顧獵蓋艱) = 壓觸製齋鏇壓範醖簾築鏇遞壓醖遞製壓鹹繭襯 (蓋積鏇廠範簾獵襯構夢, 艱鬱鑰膚艱餘鬱餘簾艱 ~ 選憲夢遞襯膚鑰壓廠遞) 更多