Pub Date : 2024-06-01Epub Date: 2024-02-27DOI: 10.1007/s00280-023-04631-7
Toshihiko Doi, Shunji Takahashi, Daisuke Aoki, Kan Yonemori, Hiroki Hara, Kosei Hasegawa, Kazuhiro Takehara, Kenichi Harano, Mayu Yunokawa, Hiroyuki Nomura, Tatsunori Shimoi, Koji Horie, Aiko Ogasawara, Shinichi Okame
Purpose: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated.
Methods: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity.
Results: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response.
Conclusion: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition.
目的:TAS-117 是一种高效、选择性口服异构泛 AKT 抑制剂,正在开发用于晚期/转移性实体瘤的治疗。该研究对其安全性、临床药理学、药物基因组学和疗效进行了调查:这项I期、开放标签、非随机、剂量递增、首次人体试验研究招募了晚期/转移性实体瘤患者,包括三个阶段(剂量递增阶段[DEP]、方案调整阶段[RMP]和安全性评估阶段[SAP])。SAP 的剂量和治疗方案在 DEP 和 RMP 中确定。研究了每日一次给药和间歇给药(服药 4 天/停药 3 天,21 天为一个周期)。主要终点是 DEP 和 RMP 第一周期的剂量限制性毒性(DLT)以及 SAP 的不良事件(AE)和药物不良反应(ADR)发生率。次要终点包括药代动力学、药效学、药物基因组学和抗肿瘤活性:在66名入组患者中,65人接受了TAS-117治疗(DEP,12人;RMP,10人;SAP,43人)。24毫克/天的间歇给药剂量未出现DLT,该剂量被选为SAP的推荐剂量。在 SAP 中,98.5% 的患者同时出现 AE 和 ADR(等级≥3,分别为 67.7% 和 60.0%)。在测试的剂量范围内(8 至 32 毫克/天),TAS-117 的药代动力学与剂量成正比,药效学分析表明磷酸化 PRAS40(AKT 的直接底物)减少。SAP中的4名患者已证实有部分反应:结论:TAS-117的口服剂量为每天一次至16毫克,间歇剂量为每天24毫克,耐受性良好。在所评估的剂量下,TAS-117的药代动力学与剂量成正比。抗肿瘤活性可能是通过抑制AKT产生的。试验注册:jRCT2080222728(2015年1月29日)。
{"title":"A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors.","authors":"Toshihiko Doi, Shunji Takahashi, Daisuke Aoki, Kan Yonemori, Hiroki Hara, Kosei Hasegawa, Kazuhiro Takehara, Kenichi Harano, Mayu Yunokawa, Hiroyuki Nomura, Tatsunori Shimoi, Koji Horie, Aiko Ogasawara, Shinichi Okame","doi":"10.1007/s00280-023-04631-7","DOIUrl":"10.1007/s00280-023-04631-7","url":null,"abstract":"<p><strong>Purpose: </strong>TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated.</p><p><strong>Methods: </strong>This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity.</p><p><strong>Results: </strong>Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response.</p><p><strong>Conclusion: </strong>Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition.</p><p><strong>Trial registration: </strong>jRCT2080222728 (January 29, 2015).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-02-25DOI: 10.1007/s00280-024-04655-7
Zhuoyuan Yu, Haifan Xu, Miao Feng, Liqun Chen
Background and objectives: Proteinuria is a common complication after the application of bevacizumab therapy in patients with metastatic colorectal cancer, and severe proteinuria can lead to discontinuation of the drug. There is a lack of sophisticated means to predict bevacizumab-induced proteinuria, so the present study aims to predict bevacizumab-induced proteinuria using peripheral venous blood samples.
Methods: A total of 122 subjects were enrolled and underwent pre-treatment plasma markers, and we followed them for six months with proteinuria as the endpoint event. We then analyzed the clinical features and plasma markers for grade ≥ 2 proteinuria occurrence using machine learning to construct a model with predictive utility.
Results: One hundred sixteen subjects were included in the statistical analysis. We found that high baseline systolic blood pressure, low baseline HGF, high baseline ET1, high baseline MMP2, and high baseline ACE1 were risk factors for the development of grade ≥ 2 proteinuria in patients with metastatic colorectal cancer who received bevacizumab. Then, we constructed a support vector machine model with a sensitivity of 0.889, a specificity of 0.918, a precision of 0.615, and an F1 score of 0.727.
Conclusion: We constructed a machine learning model for predicting grade ≥ 2 bevacizumab-induced proteinuria, which may provide proteinuria risk assessment for applying bevacizumab in patients with metastatic colorectal cancer.
{"title":"Machine learning application identifies plasma markers for proteinuria in metastatic colorectal cancer patients treated with Bevacizumab.","authors":"Zhuoyuan Yu, Haifan Xu, Miao Feng, Liqun Chen","doi":"10.1007/s00280-024-04655-7","DOIUrl":"10.1007/s00280-024-04655-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>Proteinuria is a common complication after the application of bevacizumab therapy in patients with metastatic colorectal cancer, and severe proteinuria can lead to discontinuation of the drug. There is a lack of sophisticated means to predict bevacizumab-induced proteinuria, so the present study aims to predict bevacizumab-induced proteinuria using peripheral venous blood samples.</p><p><strong>Methods: </strong>A total of 122 subjects were enrolled and underwent pre-treatment plasma markers, and we followed them for six months with proteinuria as the endpoint event. We then analyzed the clinical features and plasma markers for grade ≥ 2 proteinuria occurrence using machine learning to construct a model with predictive utility.</p><p><strong>Results: </strong>One hundred sixteen subjects were included in the statistical analysis. We found that high baseline systolic blood pressure, low baseline HGF, high baseline ET1, high baseline MMP2, and high baseline ACE1 were risk factors for the development of grade ≥ 2 proteinuria in patients with metastatic colorectal cancer who received bevacizumab. Then, we constructed a support vector machine model with a sensitivity of 0.889, a specificity of 0.918, a precision of 0.615, and an F1 score of 0.727.</p><p><strong>Conclusion: </strong>We constructed a machine learning model for predicting grade ≥ 2 bevacizumab-induced proteinuria, which may provide proteinuria risk assessment for applying bevacizumab in patients with metastatic colorectal cancer.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139943899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-11-14DOI: 10.1007/s00280-023-04617-5
Siti Nazihahasma Hassan, Farizan Ahmad
{"title":"Azithromycin in cancer treatment: envisioning the probable link of mitochondrial dysfunction and necroptosis.","authors":"Siti Nazihahasma Hassan, Farizan Ahmad","doi":"10.1007/s00280-023-04617-5","DOIUrl":"10.1007/s00280-023-04617-5","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107590315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-02-08DOI: 10.1007/s00280-023-04637-1
Andrea René Jørgensen, Mats Bue, Pelle Hanberg, Elisabeth Krogsgaard Petersen, Christina Harlev, Jakob Hansen, Thomas Baad-Hansen, Akmal Safwat, Maiken Stilling
Purpose: Doxorubicin is a widely used chemotherapeutic drug that can be administered intravenously as both a bolus infusion and a continuous infusion. The latter is believed to lower the risk of cardiotoxicity, which is a critical long-term complication of doxorubicin treatment. The local tissue concentrations of doxorubicin will be reflected in both treatment efficacy and toxicity, but very limited information is available. The aim of this study was to measure the concentration of doxorubicin after continuous and bolus infusion in tissue compartments around a typical location of a bone tumour.
Methods: Sixteen pigs (female, Danish Landrace, mean weight 77 kg) were randomized into two groups of eight. Both groups received an intravenous infusion of 150 mg doxorubicin; Group 1 received a bolus infusion (10-15 min) and Group 2 received a continuous infusion (6 h). Before infusion, microdialysis catheters were placed intravenously and in four bone tumour-relevant tissue compartments (cancellous bone, subcutaneous tissue, synovial fluid of the knee joint and muscle tissue). Sampling was done (n = 15) over 24 h, and venous blood samples were collected as a reference.
Results: Area under the concentration-time curve (AUC0-24 h) for plasma (total concentration) was significantly different between the two groups, while peak drug concentration (Cmax) was significantly higher in two compartments (plasma and synovial fluid of the knee joint) in Group 1 compared to Group 2. Overall, the unbound tissue concentrations were extremely low with values below 0.20 µg/mL.
Conclusion: The pharmacokinetic profile for doxorubicin in the investigated tissues is very similar when comparing bolus and 6 h continuous infusion.
{"title":"Doxorubicin concentrations in bone tumour-relevant tissues after bolus and continuous infusion: a randomized porcine microdialysis study.","authors":"Andrea René Jørgensen, Mats Bue, Pelle Hanberg, Elisabeth Krogsgaard Petersen, Christina Harlev, Jakob Hansen, Thomas Baad-Hansen, Akmal Safwat, Maiken Stilling","doi":"10.1007/s00280-023-04637-1","DOIUrl":"10.1007/s00280-023-04637-1","url":null,"abstract":"<p><strong>Purpose: </strong>Doxorubicin is a widely used chemotherapeutic drug that can be administered intravenously as both a bolus infusion and a continuous infusion. The latter is believed to lower the risk of cardiotoxicity, which is a critical long-term complication of doxorubicin treatment. The local tissue concentrations of doxorubicin will be reflected in both treatment efficacy and toxicity, but very limited information is available. The aim of this study was to measure the concentration of doxorubicin after continuous and bolus infusion in tissue compartments around a typical location of a bone tumour.</p><p><strong>Methods: </strong>Sixteen pigs (female, Danish Landrace, mean weight 77 kg) were randomized into two groups of eight. Both groups received an intravenous infusion of 150 mg doxorubicin; Group 1 received a bolus infusion (10-15 min) and Group 2 received a continuous infusion (6 h). Before infusion, microdialysis catheters were placed intravenously and in four bone tumour-relevant tissue compartments (cancellous bone, subcutaneous tissue, synovial fluid of the knee joint and muscle tissue). Sampling was done (n = 15) over 24 h, and venous blood samples were collected as a reference.</p><p><strong>Results: </strong>Area under the concentration-time curve (AUC<sub>0-24 h</sub>) for plasma (total concentration) was significantly different between the two groups, while peak drug concentration (C<sub>max</sub>) was significantly higher in two compartments (plasma and synovial fluid of the knee joint) in Group 1 compared to Group 2. Overall, the unbound tissue concentrations were extremely low with values below 0.20 µg/mL.</p><p><strong>Conclusion: </strong>The pharmacokinetic profile for doxorubicin in the investigated tissues is very similar when comparing bolus and 6 h continuous infusion.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11130026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX).
Methods: In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m2 (low-dose group) and 130 mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs).
Results: Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705).
Conclusions: SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.
{"title":"Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001).","authors":"Mayumi Ozawa, Jun Watanabe, Atsushi Ishibe, Koki Goto, Yoshiro Fujii, Kazuya Nakagawa, Yusuke Suwa, Hirokazu Suwa, Hidenobu Masui, Mitsutaka Sugita, Yasuhisa Mochizuki, Shigeru Yamagishi, Seiji Hasegawa, Yuki Homma, Masashi Momiyama, Takafumi Kumamoto, Ryusei Matsuyama, Kazuhisa Takeda, Masataka Taguri, Itaru Endo","doi":"10.1007/s00280-024-04648-6","DOIUrl":"10.1007/s00280-024-04648-6","url":null,"abstract":"<p><strong>Purpose: </strong>The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX).</p><p><strong>Methods: </strong>In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m<sup>2</sup>. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m<sup>2</sup> (low-dose group) and 130 mg/m<sup>2</sup> (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs).</p><p><strong>Results: </strong>Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705).</p><p><strong>Conclusions: </strong>SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-11DOI: 10.1007/s00280-024-04677-1
Yuchen Sun, Yue Cheng, Daniel L Hertz
Taxanes are a widely used class of anticancer agents that play a vital role in the treatment of a variety of cancers. However, toxicity remains a major concern of using taxane drugs as some toxicities are highly prevalent, they can not only adversely affect patient prognosis but also compromise the overall treatment plan. Among all kinds of factors that associated with taxane toxicity, taxane exposure has been extensively studied, with different pharmacokinetic (PK) parameters being used as toxicity predictors. Compared to other widely used predictors such as the area under the drug plasma concentration curve versus time (AUC) and time above threshold plasma drug concentration, maximum plasma concentration (Cmax) is easier to collect and shows promise for use in clinical practice. In this article, we review the previous research on using Cmax to predict taxane treatment outcomes. While Cmax and toxicity have been extensively studied, research on the relationship between Cmax and efficacy is lacking. Most of the articles find a positive relationship between Cmax and toxicity but several articles have contradictory findings. Future clinical trials are needed to validate the relationship between Cmax and treatment outcome and determine whether Cmax can serve as a useful surrogate endpoint of taxane treatment efficacy.
{"title":"Using maximum plasma concentration (C<sub>max</sub>) to personalize taxane treatment and reduce toxicity.","authors":"Yuchen Sun, Yue Cheng, Daniel L Hertz","doi":"10.1007/s00280-024-04677-1","DOIUrl":"10.1007/s00280-024-04677-1","url":null,"abstract":"<p><p>Taxanes are a widely used class of anticancer agents that play a vital role in the treatment of a variety of cancers. However, toxicity remains a major concern of using taxane drugs as some toxicities are highly prevalent, they can not only adversely affect patient prognosis but also compromise the overall treatment plan. Among all kinds of factors that associated with taxane toxicity, taxane exposure has been extensively studied, with different pharmacokinetic (PK) parameters being used as toxicity predictors. Compared to other widely used predictors such as the area under the drug plasma concentration curve versus time (AUC) and time above threshold plasma drug concentration, maximum plasma concentration (C<sub>max</sub>) is easier to collect and shows promise for use in clinical practice. In this article, we review the previous research on using C<sub>max</sub> to predict taxane treatment outcomes. While C<sub>max</sub> and toxicity have been extensively studied, research on the relationship between C<sub>max</sub> and efficacy is lacking. Most of the articles find a positive relationship between C<sub>max</sub> and toxicity but several articles have contradictory findings. Future clinical trials are needed to validate the relationship between C<sub>max</sub> and treatment outcome and determine whether C<sub>max</sub> can serve as a useful surrogate endpoint of taxane treatment efficacy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-02-07DOI: 10.1007/s00280-023-04620-w
Ahmed O ELKasar, Fatma Z Hussien, Hala E Abdel-Hamied, Ibrahim G Saleh, Elsayed M Mahgoup, Amr A El-Arabey, Adel R Abd-Allah
Purpose: Myelosuppressive chemotherapy-induced neutropenia (CIN) remains a major limitation of cancer treatment efficacy, necessitating very expensive supportive care. Lithium carbonate, an inexpensive drug, can increase the number of neutrophils, possibly providing an efficacious and cost-effective alternative for treating CIN. The aim of this study was to determine whether lithium therapy can attenuate chemotherapy-induced neutropenia and leukopenia in breast cancer patients.
Methods: A total of 50 breast cancer patients were enrolled in this prospective, interventional, randomized, controlled, and single-blind study. The patients were divided into two groups: a control group (group 1, N = 25 patients) and a lithium-treated (treatment) group (group 2, N = 25 patients). Group 1 patients were further subclassified into a non-neutropenic control group (N = 16) and a neutropenic control (N = 9) based on the subsequent development of severe neutropenia, or not. The control group received 4 cycles of doxorubicin or epirubicin plus cyclophosphamide followed by 2 cycles of paclitaxel. The treatment group received the same regimen as the control group as well as oral lithium carbonate throughout the chemotherapy cycles.
Results: The results showed that the absolute neutrophil count (ANC) was increased in the lithium-treated group, while it was markedly reduced in both the non-neutropenic and neutropenic control groups (by 55.56% and 65.42% post-4 chemotherapy cycles, and by 19.57% and 39.90% post-6 cycles, respectively). The same pattern of alterations was observed for the total white blood cell count in both the control and treatment groups. In addition, the incidence and period prevalence were greatly reduced in the lithium-treated group compared to non-neutropenic and neutropenic control groups.
Conclusion: Lithium therapy ameliorated chemotherapy-induced leukopenia and neutropenia in breast cancer patients. This may provide a new strategy for cost-effective treatment of CIN, particularly in Egyptian cancer patients.
{"title":"Effect of lithium on chemotherapy-induced neutropenia in Egyptian breast cancer patients; a prospective clinical study.","authors":"Ahmed O ELKasar, Fatma Z Hussien, Hala E Abdel-Hamied, Ibrahim G Saleh, Elsayed M Mahgoup, Amr A El-Arabey, Adel R Abd-Allah","doi":"10.1007/s00280-023-04620-w","DOIUrl":"10.1007/s00280-023-04620-w","url":null,"abstract":"<p><strong>Purpose: </strong>Myelosuppressive chemotherapy-induced neutropenia (CIN) remains a major limitation of cancer treatment efficacy, necessitating very expensive supportive care. Lithium carbonate, an inexpensive drug, can increase the number of neutrophils, possibly providing an efficacious and cost-effective alternative for treating CIN. The aim of this study was to determine whether lithium therapy can attenuate chemotherapy-induced neutropenia and leukopenia in breast cancer patients.</p><p><strong>Methods: </strong>A total of 50 breast cancer patients were enrolled in this prospective, interventional, randomized, controlled, and single-blind study. The patients were divided into two groups: a control group (group 1, N = 25 patients) and a lithium-treated (treatment) group (group 2, N = 25 patients). Group 1 patients were further subclassified into a non-neutropenic control group (N = 16) and a neutropenic control (N = 9) based on the subsequent development of severe neutropenia, or not. The control group received 4 cycles of doxorubicin or epirubicin plus cyclophosphamide followed by 2 cycles of paclitaxel. The treatment group received the same regimen as the control group as well as oral lithium carbonate throughout the chemotherapy cycles.</p><p><strong>Results: </strong>The results showed that the absolute neutrophil count (ANC) was increased in the lithium-treated group, while it was markedly reduced in both the non-neutropenic and neutropenic control groups (by 55.56% and 65.42% post-4 chemotherapy cycles, and by 19.57% and 39.90% post-6 cycles, respectively). The same pattern of alterations was observed for the total white blood cell count in both the control and treatment groups. In addition, the incidence and period prevalence were greatly reduced in the lithium-treated group compared to non-neutropenic and neutropenic control groups.</p><p><strong>Conclusion: </strong>Lithium therapy ameliorated chemotherapy-induced leukopenia and neutropenia in breast cancer patients. This may provide a new strategy for cost-effective treatment of CIN, particularly in Egyptian cancer patients.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Retraction Note: Effectiveness and safety of sorafenib for renal cell, hepatocellular and thyroid carcinoma: pooled analysis in patients with renal impairment.","authors":"Mototsugu Oya, Shuichi Kaneko, Tsuneo Imai, Toshiaki Tsujino, Toshiyuki Sunaya, Yutaka Okayama","doi":"10.1007/s00280-023-04587-8","DOIUrl":"10.1007/s00280-023-04587-8","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10321844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2024-03-23DOI: 10.1007/s00280-024-04658-4
Marco Orleni, Jan H Beumer
Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies.
{"title":"Pharmacology and pharmacokinetics of tazemetostat.","authors":"Marco Orleni, Jan H Beumer","doi":"10.1007/s00280-024-04658-4","DOIUrl":"10.1007/s00280-024-04658-4","url":null,"abstract":"<p><p>Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2024-01-27DOI: 10.1007/s00280-023-04633-5
Bin Fan, Ghassan K Abou-Alfa, Andrew X Zhu, Shuchi S Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, Hua Yang
Purpose: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.
Methods: Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 - 2, pre-dose and 2 h post-dose on D15 of C1 - 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.
Results: PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).
Conclusion: Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma.
Clinical trial registration: NCT02989857 Registered February 20, 2017.
{"title":"Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study.","authors":"Bin Fan, Ghassan K Abou-Alfa, Andrew X Zhu, Shuchi S Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, Hua Yang","doi":"10.1007/s00280-023-04633-5","DOIUrl":"10.1007/s00280-023-04633-5","url":null,"abstract":"<p><strong>Purpose: </strong>Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.</p><p><strong>Methods: </strong>Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 - 2, pre-dose and 2 h post-dose on D15 of C1 - 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.</p><p><strong>Results: </strong>PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [T<sub>max</sub>] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).</p><p><strong>Conclusion: </strong>Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma.</p><p><strong>Clinical trial registration: </strong>NCT02989857 Registered February 20, 2017.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139566871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}