The main aims of this clinical study are to find out the maximum dose that can be given safely to patients, the potential side effects of the drug and how they can be managed and what happens to AZD3965 inside the body.
AZD3965 is a type of drug called a monocarboxylate transporter 1 inhibitor which is being used to stop the growth of cancer cells and kill cancer cells by blocking the action of one of the proteins involved in moving chemical compounds in and out of the cells of the body. This will be the first time that this type of drug has been given to patients.
The drug is a capsule and is taken daily. The study is in two parts. In Part 1 of the study, small groups of patients are treated at increasing doses to find the highest safe dose and best dose to give to patients in Part 2 of the study. It is planned that 40 patients will be entered into Part 1 of the trial.
In Part 2, the dose found to be safe in Part 1 is given to patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). It is planned that 20 patients will be entered into Part 2 of the trial.
Patients will need to visit the hospital weekly for two months and then every fortnight. Patients will have regular blood and urine tests, scans, heart traces and eye tests amongst other clinical tests. Research blood samples will also be taken to look at what happens to the drug inside the body. Treatment is planned to be given for up to 6 months, but patients benefiting from treatment will be able to keep having it for as long as they continue to benefit. It is important to explain that this is the first study of this drug and patients will have advanced cancer so it is unlikely that patients will benefit directly from taking part but the study may help improve future treatment of cancer.

开始日期2013-04-23

申办/合作机构

Cancer Research UK

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100 项与 AZD-3965 相关的临床结果

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100 项与 AZD-3965 相关的转化医学

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100 项与 AZD-3965 相关的专利（医药）

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102

项与 AZD-3965 相关的文献（医药）

2025-04-01·Biochemical and Biophysical Research Communications

Lactate dehydrogenase B deficiency-dependent hyperlactatemia coordinates with necroptosis to worsen septic liver and kidney injuries

Article

作者: Zhu, Hai-Ping ; Mo, Shi-Jing ; Qiu, Chen ; Jin, Shu-Wen ; Lai, Jun-Mei ; Jia, Yu ; Ye, Xiang-Ming ; Zhu, Ge ; Shen, Ye ; Yang, Xiang-Hong

Hyperlactatemia is intimately correlated with severity and poor prognosis of patients with sepsis. However, little experimental evidence on this process is known. We report here that lactate dehydrogenase B (LDHB), the glycolytic enzyme that catalyzes conversion of lactate to pyruvate, is transcriptionally downregulated in blood samples of hyperlactatemic patients, while mice receiving lactate injection have reduced LDHB activity in liver and kidney. LDHB knockout (Ldhb^-/-) mice with hyperlactatemia are vulnerable to lethality, hypotension and vascular leakage. The hyperlactatemic Ldhb^-/- mice develop severe liver and kidney injuries accompanied by increased hepatic and renal SLC16A1 abundance but unaltered morphology. Pharmacological targeting of SLC16A1 with AZD3965 in Ldhb^-/- mice rescues the hyperlactatemia-induced lethality, liver and kidney injuries. Loss of LDHB renders hyperlactatemia, lethality, vascular leakage, liver and kidney injuries in response to abdominal sepsis. AZD3965 treatment partially abrogates liver and kidney injuries of septic Ldhb^-/- mice without affecting necrosis. Blockade of necroptosis significantly protects Ldhb^-/- mice against septic liver and kidney injuries, enabling a compensation towards the therapeutic efficacy of AZD3965. Our study together unearth the coordination of hyperlactatemia and necroptosis in septic liver and kidney injuries in the context of LDHB deficiency, and support further investigation of combined targeting SLC16A1 and necroptosis for clinical treatment of sepsis with low LDHB activity.

2025-03-01·Journal of Biological Chemistry

Glyceraldehyde-3-Phosphate Dehydrogenase/1,3-Bisphosphoglycerate-NADH as Key Determinants in Controlling Human Retinal Endothelial Cellular Functions: Insights from Glycolytic Screening

Article

作者: Yumnamcha, Thangal ; Singh, Lalit Pukhrambam ; Eltanani, Shaimaa ; Naghdi, Armaan ; Shawky, Mohamed ; Awad, Ahmed M ; Ibrahim, Ahmed S ; Oska, Nicole

Maintaining barrier integrity, along with cell adhesion to the extracellular matrix and the subsequent process of cell spreading, are essential functions of endothelial cells, including human retinal endothelial cells (HRECs). Disruptions in these processes can lead to vision-threatening conditions like diabetic retinopathy. However, the bioenergetic mechanisms that regulate HREC barrier function and cell spreading remain incompletely understood. This study investigates the role of lower glycolytic components in modulating these critical functions of HRECs. In vitro, Electric Cell-Substrate Impedance Sensing (ECIS) technology was used to measure real-time changes in HREC barrier integrity (electrical resistance) and cell spreading (capacitance). Pharmacological inhibitors targeting lower glycolytic components were tested: heptelidic acid for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), NG-52 for phosphoglycerate kinase (PGK), shikonin for pyruvate kinase M (PKM), galloflavin for lactate dehydrogenase (LDH), AZD3965 for lactate transporter (MCT-1), and MSDC-0160 for the mitochondrial pyruvate carrier (MPC). GAPDH knockdown was performed using siRNA, and cell viability was assessed via lactate dehydrogenase (LDH) release assays. For in vivo studies, wild-type C57BL/6J mice received intravitreal injections of heptelidic acid, while control mice received vehicle (DMSO). Retinal vascular permeability was assessed by fluorescein angiography (FA) and retinal albumin leakage. The most significant decrease in electrical resistance and increase in capacitance of HRECs were observed following the dose-dependent inhibition of GAPDH and the resulting reduction in 1,3-bisphosphoglycerate (1,3-BPG) and NADH by heptelidic acid. LDH level analysis at 24-48 hours post-treatment with heptelidic acid (1 and 10 μM) showed no significant difference compared to controls, indicating that the observed disruption of HREC functionality was not due to cell death. Supporting these findings, inhibition of downstream glycolytic steps that result in the accumulation of 1,3-BPG and NADH, such as treatment with NG-52 for PGK or shikonin for PKM, led to a significant increase in electrical resistance and a decrease in cell capacitance. Furthermore, GAPDH knockdown via siRNA also led to a significant decrease in cellular resistance in HRECs. In vivo, FA imaging demonstrated that intravitreal injection of heptelidic acid led to significant retinal vascular leakage, further supported by increased albumin extravasation in treated eyes. Conversely, pharmacological inhibition of other lower glycolytic components, including LDH, MCT, and MPC, did not significantly alter HREC barrier function or spreading behavior. This study highlights the distinct roles of lower glycolytic components in regulating HREC functionality. GAPDH and its downstream products (1,3-BPG and NADH) are shown to play a pivotal role in maintaining barrier integrity and promoting HREC adhesion and spreading. These findings guide the development of targeted interventions that modulate HREC bioenergetics to treat endothelial dysfunction in various retinal disorders, while minimizing potential adverse effects on healthy endothelial cells.

2025-02-01·Molecular Imaging and Biology

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-Induced Cardiotoxicity

Article

作者: Manzo, Onorina L ; Jeitner, Thomas M ; Babich, John W ; Kelly, James M ; Azcona, Juan A ; Lee, Chul-Hee ; Fung, Edward K ; Di Lorenzo, Annarita ; Amor-Coarasa, Alejandro ; Wacker, Anja S

AbstractPurposeTreatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[18F]fluoropropionic acid ([18F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin.ProceduresCardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [18F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations.ResultsSignificantly higher cardiac [18F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [18F]FPA in tissues other than the heart. Co-administration of [18F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. Conclusions[18F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

项与 AZD-3965 相关的新闻（医药）

2023-03-28

·生物谷

高氧条件下通过抑制关键信号轴延缓肿瘤生长

为了帮助肿瘤生长和扩散，癌症细胞改变细胞外环境的化学成分，并通过释放代谢物、生长因子和趋化因子重新规划其微环境。反过来，微环境可以对癌症细胞施加各种非细胞自主压力，包括营养和缺氧以及细胞外空间酸化。为了帮助肿瘤生长和扩散，癌症细胞改变细胞外环境的化学成分，并通过释放代谢物、生长因子和趋化因子重新规划其微环境。反过来，微环境可以对癌症细胞施加各种非细胞自主压力，包括营养和缺氧以及细胞外空间酸化。癌症细胞对葡萄糖和谷氨酰胺的高需求和利用导致乳酸的过度生产和胞外转运，这被认为是导致肿瘤酸中毒的重要因素。正常细胞的细胞内pH（pHi）通常在~7.2左右，低于细胞外pH（pHe）~7.4。相比之下，癌症细胞通常表现出较高的pHi（>7.4）和较低的pHe（6.7-7.1）。这种特殊的pH平衡在肿瘤发展中的详细作用尚不清楚，但最新证据表明，它可能与癌症细胞增殖、避免凋亡、缺氧适应和细胞外基质重塑有关。图片来源：https://doi.org/10.1016/j.redox.2023.102647 近日，来自同济大学的研究者们在Redox Biol.杂志上发表了题为“Long-term exposure to house dust mites accelerates lung cancer development in mice”的文章，该研究显示，高氧可以抑制MYC/MCT1轴，并导致乳酸的积累和细胞内酸化，从而延缓肿瘤生长和转移。吸入性高氧（IH）在肿瘤学中的风险和前景仍有争议，尤其是对于癌症患者。越来越多的证据表明，高氧暴露与肿瘤微环境有关。然而，IH在癌症细胞酸碱平衡中的具体作用尚不清楚。本研究在H1299和A549细胞中系统地评估了60%氧气暴露对细胞内外pH值的影响。研究结果表明，高氧暴露会降低细胞内pH值，这可能会降低癌症细胞的增殖、侵袭和上皮-间充质转化。RNA测序、蛋白质印迹和PCR分析表明，单羧酸盐转运蛋白1（MCT1）在60%的氧气暴露下介导H1299和A549细胞的细胞内乳酸积累和细胞内酸化。体内研究进一步证明，MCT1基因敲除可显著降低癌症的生长、侵袭和转移。萤光素酶和ChIP-qPCR测定的结果进一步证实了MYC是MCT1的转录因子，并且PCR和Western印迹测定证实了在高氧条件下MYC被下调。 MCT1敲低可抑制体内肺肿瘤的生长和转移。图片来源：https://doi.org/10.1016/j.redox.2023.102647 综上所述，高氧暴露可以抑制MYC/MCT1轴，导致乳酸积累和细胞内酸化，这与癌症的生长和转移密切相关。本研究是对pHi直接靶向治疗癌症可行性的一次突破性尝试，为IH联合AZD3965治疗肺癌提供了理论依据。（生物谷 Bioon.com）参考文献 Xiucheng Liu et al. Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC/MCT1 axis in lung cancer. Redox Biol. 2023 ay;61:102647. doi: 10.1016/j.redox.2023.102647.

临床研究申请上市临床结果AACR会议

100 项与 AZD-3965 相关的药物交易

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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


NCT01791595 (CTgov)	临床1期	实体瘤 \| 伯基特淋巴瘤 \| 弥漫性大B细胞淋巴瘤 \| 晚期癌症	53	AZD3965 (AZD3965 Cohort 1 (5 mg OD))	鏇醖醖獵網鑰蓋醖鹽窪(廠衊淵窪鹽窪繭觸衊窪) = 鏇鹹蓋構遞窪積願憲遞選襯範廠齋衊願築積顧 (構顧衊觸鏇鹹鏇觸廠築, 鏇衊衊鬱壓憲積廠鏇壓 ~ 淵膚選壓餘鬱醖簾製鬱) 更多	-	2022-04-11
NCT01791595 (CTgov)	临床1期	实体瘤 \| 伯基特淋巴瘤 \| 弥漫性大B细胞淋巴瘤 \| 晚期癌症	53	AZD3965 (AZD3965 Cohort 2 (10 mg OD))	鏇醖醖獵網鑰蓋醖鹽窪(廠衊淵窪鹽窪繭觸衊窪) = 膚簾壓鹹齋餘齋構鑰顧選襯範廠齋衊願築積顧 (構顧衊觸鏇鹹鏇觸廠築, 鹽網衊顧鑰簾醖獵範壓 ~ 製膚選餘醖淵鑰範淵膚) 更多	-	2022-04-11
NCT01791595 (ASCO2021)	临床1期	伯基特淋巴瘤 \| 弥漫性大B细胞淋巴瘤	11	AZD3965 10mg bd	(製鏇糧製醖築鬱築襯獵) = no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported 鏇製製選齋鹽壓廠繭網 (簾鬱範範鏇衊夢糧鬱壓 ) 更多	积极	2021-05-28
NCT01791595 (ASCO2017)	临床1期	晚期恶性实体瘤	35	AZD3965	(遞鑰膚艱觸夢艱製製獵) = 膚憲範鑰夢糧簾願鹹壓膚憲襯襯壓築鬱顧衊繭 (遞淵顧醖構簾夢鹽鑰蓋 )	-	2017-05-30