Integrinα_(v)β_(3)is overexpressed in various tumor cells and angiogenesis.To date,no drug has been proven to target it for therapy.A first-in-human study was designed to investigate the safety,pharmacokinetics,and ...Integrinα_(v)β_(3)is overexpressed in various tumor cells and angiogenesis.To date,no drug has been proven to target it for therapy.A first-in-human study was designed to investigate the safety,pharmacokinetics,and dosimetry of^(177)Lu-AB-3PRGD2,a novel integrinα_(v)β_(3)-targeting radionuclide drug with an albumin-binding motif to optimize the pharmacokinetics.Ten patients(3 men,7 women;aged 45±16 years)with integrinα_(v)β_(3)-avid tumors were recruited to accept^(177)Lu-AB-3PRGD2 injection in a dosage of 1.57±0.08 GBq(42.32±2.11 mCi),followed by serial scans to obtain its dynamic distribution in the body.Safety tests were performed before and every 2 weeks after the treatment for 6-8 weeks.No adverse event over grade 3 was observed.^(177)Lu-AB-3PRGD2 was excreted mainly through the urinary system,with intense radioactivity in the kidneys and bladder.Moderate distribution was found in the liver,spleen,and intestines.The estimated blood half-life was 2.85±2.17 h.The whole-body effective dose was 0.251±0.047 mSv/MBq.The absorbed doses were 0.157±0.032 mGy/MBq in red bone marrow and 0.684±0.132 mGy/MBq in kidneys.This first-in-human study of^(177)Lu-AB-3PRGD2 treatment indicates its promising potential for targeted radionuclide therapy of integrinα_(v)β_(3)-avid tumors.It merits further studies in more patients with escalating doses and multiple treatment courses.展开更多
Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have sh...Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.展开更多
Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated ...Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).展开更多
Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subje...Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe punishment.He was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate overnight.This myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.展开更多
基金supported by Chinese Academy of Medical Science Innovation Fund for Medical Sciences(2022-I2M-2-002)the National High-Level Hospital Clinical Research Funding(2022-PUMCH-D-002,China)+2 种基金Clinical and translational medicine research project of the Chinese Academy of Medical Sciences(2022-I2M-C&T-A-008,China)the National Natural Science Foundation of China(82272046)the Fundamental Research Funds for the Central Universities(3332023124,China).
文摘Integrinα_(v)β_(3)is overexpressed in various tumor cells and angiogenesis.To date,no drug has been proven to target it for therapy.A first-in-human study was designed to investigate the safety,pharmacokinetics,and dosimetry of^(177)Lu-AB-3PRGD2,a novel integrinα_(v)β_(3)-targeting radionuclide drug with an albumin-binding motif to optimize the pharmacokinetics.Ten patients(3 men,7 women;aged 45±16 years)with integrinα_(v)β_(3)-avid tumors were recruited to accept^(177)Lu-AB-3PRGD2 injection in a dosage of 1.57±0.08 GBq(42.32±2.11 mCi),followed by serial scans to obtain its dynamic distribution in the body.Safety tests were performed before and every 2 weeks after the treatment for 6-8 weeks.No adverse event over grade 3 was observed.^(177)Lu-AB-3PRGD2 was excreted mainly through the urinary system,with intense radioactivity in the kidneys and bladder.Moderate distribution was found in the liver,spleen,and intestines.The estimated blood half-life was 2.85±2.17 h.The whole-body effective dose was 0.251±0.047 mSv/MBq.The absorbed doses were 0.157±0.032 mGy/MBq in red bone marrow and 0.684±0.132 mGy/MBq in kidneys.This first-in-human study of^(177)Lu-AB-3PRGD2 treatment indicates its promising potential for targeted radionuclide therapy of integrinα_(v)β_(3)-avid tumors.It merits further studies in more patients with escalating doses and multiple treatment courses.
基金supported by the National Natural Science Foundation of China(No.82071961)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare,Key Scientific Research Program for Yong Scholars in Fujian(No.2021ZQNZD016,China)+5 种基金Fujian Natural Science Foundation for Distinguished Young Scholars(No.2022D005,China)Innovation of Science and Technology,Fujian Province(No.2021Y9134,China)National University of Singapore(No.NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(No.MOH-001388-00,MOH-001041,CG21APR1005,Singapore)Singapore Ministry of Education(No.MOE-000387-00,Singapore)National Research Foundation(No.NRF-000352-00,Singapore).
文摘Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.
文摘Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).
基金supported by the National Natural Science Foundation of China(Nos.82074068,82373912,82300685)the National Key R&D Program of China(No.2023YFD1601400)+3 种基金the Fundamental Research Funds for the Central Universities(No.2632022YC04)Jiangsu Outstanding Youth Fund Project(No.BK20231535)the Natural Science Foundation of Jiangsu Province(No.BK20221052)the Jiangsu Funding Program for Excellent Postdoctoral Talent(No.2022ZB286).
文摘Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe punishment.He was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate overnight.This myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.
