المؤلفون: Yasutoshi Kuboki, Yuko Mori, Yoichi Naito, Takahiro Kogawa, Nobuaki Matsubara, Shigeyuki Toyoizumi, Takashi Nagasawa, Kenichi Harano, Masafumi Ikeda, Natsuki Hori

المصدر: Investigational New Drugs

مصطلحات موضوعية: Adult, 0301 basic medicine, medicine.medical_specialty, Maximum Tolerated Dose, Anemia, Talazoparib, Cmax, Antineoplastic Agents, Phase 1, Poly(ADP-ribose) Polymerase Inhibitors, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Asian People, Japan, Pharmacokinetics, Phase I Studies, Neoplasms, Internal medicine, medicine, Maculopapular rash, Clinical endpoint, Humans, Pharmacology (medical), Neoplasm Metastasis, Adverse effect, Stomatitis, Aged, Pharmacology, Dose-Response Relationship, Drug, business.industry, Middle Aged, medicine.disease, PARP inhibitor, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Phthalazines, Safety, Neoplasm Grading, medicine.symptom, business

الوصف: SummaryBackground: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::19ed123337d8369dfb1f4c651d0abc67Test
https://doi.org/10.1007/s10637-021-01120-7Test

المؤلفون: Lei Huo, Gaiane M. Rauch, Alyson Clayborn, Tanbin Rahman, Pamela McCarthy, David Ramirez, Elizabeth Ravenberg, Sadia Saleem, Stacy L. Moulder, Clinton Yam, W. Fraser Symmans, Jason B White, James Stec, Sausan Abouharb, Bora Lim, Jennifer K. Litton, Senthil Damodaran, Meghan Sri Karuturi, Ryan Sun

المصدر: Investigational New Drugs. 39:509-515

مصطلحات موضوعية: Adult, 0301 basic medicine, Oncology, medicine.medical_specialty, Immunoconjugates, Disease Response, Phases of clinical research, Triple Negative Breast Neoplasms, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Folate Receptor 1, Maytansine, Pharmacology (medical), Prospective Studies, Adverse effect, Triple-negative breast cancer, Pharmacology, business.industry, medicine.disease, Clinical trial, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), Immunohistochemistry, Female, business, Progressive disease

الوصف: Folate receptor alpha (FRα) has been reported to be expressed in up to 80% of triple-negative breast cancers (TNBC) with limited expression in normal tissues, making it a promising therapeutic target. Mirvetuximab soravtansine (mirvetuximab-s) is an antibody drug conjugate which has shown promise in the treatment of FRα-positive solid tumors in early phase clinical trials. Herein, are the results of the first prospective phase II trial evaluating mirvetuximab-s in metastatic TNBC. Patients with advanced, FRα-positive TNBC were enrolled on this study. Mirvetuximab-s was administered at a dose of 6.0 mg/kg every 3 weeks. 96 patients with advanced TNBC consented for screening. FRα staining was performed on tumor tissue obtained from 80 patients. The rate of FRα positivity by immunohistochemistry was 10.0% (8/80). Two patients were treated on study, with best overall responses of stable disease in one and progressive disease in the other. Adverse events were consistent with earlier studies. The study was terminated early due to the low rate of FRα positivity in the screened patient population and lack of disease response in the two patients treated. The observed rate of FRα positivity was considerably lower than previously reported and none of the patients had a partial or complete response. Treatment with mirvetuximab-s should only be further explored in TNBC if an alternate biomarker strategy is developed for patient selection on the basis of additional preclinical data.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0e6b9d56eaf08effcaff310abab6d9d7Test
https://doi.org/10.1007/s10637-020-00995-2Test

المؤلفون: Sujata Rao, Rakesh Verma, Todd M. Bauer, Aung Naing, J. Leveque, Raid Aljumaily, Zev A. Wainberg, Johanna C. Bendell, J. Randolph Hecht, Gerald Steven Falchook, Martin Oft, Annie Hung, Karen A. Autio, Shubham Pant, Jeffrey R. Infante, Navneet Ratti, Deborah J. Wong, Manish R. Patel, Kyriakos P. Papadopoulos, Peter VanVlasselaer, Milind Javle

المصدر: Investigational new drugs, vol 39, iss 1
Invest New Drugs

مصطلحات موضوعية: 0301 basic medicine, Oncology, Organoplatinum Compounds, Metastatic pancreatic adenocarcinoma, Leucovorin, Phases of clinical research, Kaplan-Meier Estimate, Polyethylene Glycols, 0302 clinical medicine, FOLFOX, Antineoplastic Combined Chemotherapy Protocols, Pharmacology (medical), 6.2 Cellular and gene therapies, Cancer, education.field_of_study, Pharmacology and Pharmaceutical Sciences, Middle Aged, Progression-Free Survival, Interleukin-10, Tolerability, Pancreatic Ductal, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, IL-10, Fluorouracil, Pegilodecakin, Drug, Carcinoma, Pancreatic Ductal, medicine.drug, Adult, medicine.medical_specialty, Clinical Trials and Supportive Activities, Population, Phase 1, Article, Dose-Response Relationship, Pancreatic Cancer, 03 medical and health sciences, Rare Diseases, Clinical Research, Internal medicine, medicine, Humans, Oncology & Carcinogenesis, Pegylated IL-10, Adverse effect, education, Response Evaluation Criteria in Solid Tumors, Neoplasm Staging, Aged, Pharmacology, Dose-Response Relationship, Drug, business.industry, Carcinoma, Evaluation of treatments and therapeutic interventions, digestive system diseases, Oxaliplatin, Pancreatic Neoplasms, Regimen, 030104 developmental biology, Tumor progression, Digestive Diseases, business

الوصف: Background Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited and checkpoint blockade inhibitors have been disappointing in this disease. Pegilodecakin has demonstrated single agent anti-tumor activity in immune-sensitive tumors. Phase 1 and preclinical data indicate synergy of pegilodecakin with 5-FU and platins. We assessed the safety and activity of pegilodecakin+FOLFOX in patients with PDAC. Methods IVY (NCT02009449) was an open-label phase 1b trial in the United States. Here we report on all enrolled patients from cohort C. Heavily pretreated patients were treated with pegilodecakin (self-administered subcutaneously daily at 2.5, 5, or 10μg/kg) + 5-flurouracil/leucovorin/oxaliplatin (FOLFOX), dosed per manufacturers prescribing information, until tumor progression. Eligible patients had measurable disease per immune-related response criteria (irRC), were ≥ 18years of age, and had ECOG performance status of 0 or 1. Patients were evaluated for primary(safety) and secondary (tumor response per irRC) endpoints. Results From 5 August 2014-12 July 2016, 39 patients enrolled in cohort C. All patients were evaluable for safety. In this advanced population, regimen had manageable toxicities with no immune-related adverse events (irAEs) greater than grade 1. The most common grade 3/4/5 TEAEs were thrombocytopenia (21[53.8%] of 39) and anemia (17[43.6%] of 39). In evaluable PDAC patients, the best overall response of pegilodecakin+FOLFOX was 3(14%) with CRs in 2(9%) patients. Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10-42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA).

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d69d0ddd9f3551a8ca0a4d0daab7d846Test
https://doi.org/10.1007/s10637-020-01000-6Test

المؤلفون: M. Phillip DeYoung, James Vasquez, Vladimir Kostorov, Sergey Orlov, David Bellovin, Pilar Garrido López, Evgeny Levchenko, Li Yan, Shirish M. Gadgeel, Hedy L. Kindler, Jose Manuel Trigo, Manuel Domine, Marjorie G. Zauderer, Jan H.M. Schellens, Dean A. Fennell, Xiaowei Wang, Katherine Baker-Neblett, Santiago Viteri, Daniel Morgensztern, Emilie M.J. van Brummelen, Johan Vansteenkiste, Ionel Mitrica

المصدر: Invest New Drugs

مصطلحات موضوعية: Mesothelioma, Male, 0301 basic medicine, Oncogene Proteins, Fusion, Ligands, Gastroenterology, Hyperphosphatemia, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, FGF, Pharmacology (medical), Aged, 80 and over, Middle Aged, Treatment Outcome, Pemetrexed, Oncology, 030220 oncology & carcinogenesis, Female, Fibroblast Growth Factor 2, medicine.drug, Adult, medicine.medical_specialty, Combination therapy, Recombinant Fusion Proteins, Antineoplastic Agents, Phase 1, Article, 03 medical and health sciences, Pharmacokinetics, Internal medicine, medicine, Humans, Receptor, Fibroblast Growth Factor, Type 1, Adverse effect, Aged, Pharmacology, Cisplatin, business.industry, Mesothelioma, Malignant, Cancer, medicine.disease, 030104 developmental biology, Immunoglobulin G, Ligand trap, business

الوصف: BACKGROUND: Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. METHODS: A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. RESULTS: 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1–56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4–65.1), and the median PFS was 7.4 months (95% CI: 6.7–13.4). Four patients had disease control for over 1 year, and three were still ongoing. CONCLUSION: At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2f79fa27ba3514b5c0a71da97b74f5a9Test
https://doi.org/10.1007/s10637-019-00783-7Test

المؤلفون: Xuejing Wang, Katherine M Bell-McGuinn, Jimmy Hwang, Johanna C. Bendell, Hans Christian Reinhardt, Daphne L. Farrington, Celine Pitou, Helge Bischoff, Robert M. Campbell, Thomas Zander, Scott M. Hynes, Philip W. Iversen, Michael Thomas

المصدر: Investigational New Drugs. 38:1145-1155

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Pyridines, Population, Antineoplastic Agents, Models, Biological, p38 Mitogen-Activated Protein Kinases, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Pharmacology (medical), Lung cancer, Adverse effect, education, Protein Kinase Inhibitors, Aged, Pharmacology, education.field_of_study, business.industry, Imidazoles, Cancer, Common Terminology Criteria for Adverse Events, Middle Aged, medicine.disease, Treatment Outcome, 030104 developmental biology, Response Evaluation Criteria in Solid Tumors, Pyrazines, 030220 oncology & carcinogenesis, Checkpoint Kinase 1, Pyrazoles, Ralimetinib, Female, business, Febrile neutropenia

الوصف: Purpose The primary objective was to determine the recommended Phase 2 dose (RP2D) of checkpoint kinase 1 inhibitor, prexasertib, in combination with the p38 mitogen-activated protein kinase inhibitor, ralimetinib, which may be safely administered to patients with advanced cancer. Methods This Phase 1, nonrandomized, open-label, dose-escalation study of prexasertib+ralimetinib included patients with advanced and/or metastatic cancer, followed by a planned cohort expansion in patients with colorectal or non-small-cell lung cancer with KRAS and/or BRAF mutations. Intravenous prexasertib was administered at 60 mg/m2 (days 1 and 15 of a 28-day cycle), together with oral ralimetinib every 12 h (days 1 to 14 at 100 mg [Cohort 1, n = 3] or 200 mg [Cohort 2, n = 6]). Dose escalations for each agent were planned using a model-based 3 + 3 escalation paradigm. Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0X. Tumor response was determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results Nine patients were treated; 3 experienced dose-limiting toxicities, all in Cohort 2, prohibiting further dose escalation. The most common ≥Grade 3 adverse event was neutrophil count decreased; other reported ≥Grade 3 hematological toxicities included febrile neutropenia and anemia. The pharmacokinetics of prexasertib+ralimetinib was comparable to the monotherapy population profile for each agent. One patient achieved a best overall response of stable disease (for 2 cycles); there were no complete/partial responses. Conclusions This study did not achieve its primary objective of establishing an RP2D of combination prexasertib + ralimetinib that could be safely administered to patients with advanced cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8e75a04ddc23ef75c870beb94be16d9dTest
https://doi.org/10.1007/s10637-019-00873-6Test

المؤلفون: David Dai, Shuchi Sumant Pandya, Ingo K. Mellinghoff, Maeve A. Lowery, Erika Manyak, Patrick Y. Wen, Bin Fan, Lipika Goyal, Molly Prahl Judge, Sam Agresta, Tara Nimkar, Liewen Jiang, Guowen Liu, William D. Tap, Hua Yang, Camelia Gliser

المصدر: Investigational New Drugs

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, IDH1, Pyridines, Glycine, 2-hydroxyglutarate, Administration, Oral, Antineoplastic Agents, Pharmacology, IDH2, Glutarates, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Glioma, Phase I Studies, Neoplasms, medicine, Humans, Pharmacology (medical), Aged, Aged, 80 and over, CYP3A4, Dose-Response Relationship, Drug, business.industry, Isocitrate dehydrogenase 1 inhibitor, Middle Aged, medicine.disease, Isocitrate Dehydrogenase, 030104 developmental biology, Oncology, Ivosidenib, Pharmacodynamics, 030220 oncology & carcinogenesis, Concomitant, Mutation, Female, Chondrosarcoma, business

الوصف: Summary Background Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD. PK and PD were assessed using validated liquid chromatography-tandem mass spectrometry assays. Results Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40–102 h after single dose). Exposure increased less than dose proportionally. Steady state was reached by day 15, with moderate accumulation across all tumors (1.5- to 1.7-fold for area-under-the-curve at 500 mg QD). None of the intrinsic and extrinsic factors assessed affected ivosidenib exposure, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. After multiple doses in patients with cholangiocarcinoma or chondrosarcoma, plasma 2-HG was reduced by up to 98%, to levels seen in healthy subjects. Exposure-response relationships for safety and efficacy outcomes were flat across the doses tested. Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500 mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors. Trial RegistrationClinicalTrials.gov (NCT02073994).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0cb8d1211dda7c32ea032d7647d9a74aTest
http://europepmc.org/articles/PMC7066280Test

المؤلفون: Anthony W. Tolcher, Kyriakos P. Papadopoulos, Rashmi Chugh, David Smith, Robert Joseph Stagg, Ann M. Kapoun, Amita Patnaik, Min Wang, Lu Xu, Jakob Dupont

المصدر: Investigational New Drugs

مصطلحات موضوعية: 0301 basic medicine, Adult, Diarrhea, Male, medicine.medical_specialty, Abdominal pain, Tarextumab, Maximum Tolerated Dose, Nausea, Vomiting, Antineoplastic Agents, Phase 1, Gastroenterology, Antibodies, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, Phase I Studies, Neoplasms, medicine, Humans, Pharmacology (medical), Receptor, Notch2, Adverse effect, Receptor, Notch3, Fatigue, Aged, Pharmacology, Aged, 80 and over, business.industry, Antibodies, Monoclonal, Middle Aged, Notch inhibition, Anorexia, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Pharmacodynamics, Toxicity, Every Three Weeks, Female, medicine.symptom, business, Transcriptome

الوصف: Summary Purpose This Phase I trial evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of tarextumab (OMP-5948), a novel cross-reactive antibody which binds and selectively inhibits signaling via both Notch2 and Notch3, in adult patients with advanced malignancies. Methods Standard 3 + 3 design with tarextumab 0.5, 1, 2.5, or 5 mg/kg weekly, or 5, 7.5, or 10 mg/kg every other week, or 7.5 mg every 3 weeks. Dose-limiting toxicities (DLT) were assessed during the first 28 days. Results Forty-two patients received tarextumab (21 weekly, 15 every other week, 6 every three weeks). 2/6 subjects at the 5 mg/kg weekly dose, 2/3 at 10 mg/kg every other week, and 0/6 at 7.5 mg/kg every three weeks had a DLT. The maximum tolerated dose (MTD) was 2.5 mg/kg weekly, and 7.5 mg/kg on the every other and every three week schedules. Gastrointestinal (GI) toxicity was the most common adverse event with diarrhea (81%), fatigue (48%), nausea (45%), anorexia (38%), and vomiting (38%) and abdominal pain and constipation (24% each). Biomarker analysis showed regulation of stem cell and Notch gene signaling. Conclusion Tarextumab was generally well-tolerated at doses <2.5 mg weekly and 7.5 mg/kg every other and every third week. Diarrhea was dose-limiting above these levels, but relatively easily managed at lower doses. Inhibition of Notch pathway signaling was demonstrated at these doses. ClinicalTrials.gov Identifier: NCT01277146.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ab597136745efa35e8542d8038e7b360Test
http://europepmc.org/articles/PMC6647865Test

المؤلفون: Sanjay Goel, Audrey E. Kam, Ioannis Mantzaris, Santiago Aparo, Andreas Kaubisch, M. H. Ghalib, Gopichand Pendurti, Jennifer W. Chuy, Umang Shah, Imran Chaudhary, Lakshmi Rajdev

المصدر: Invest New Drugs

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Maximum Tolerated Dose, Colorectal cancer, Disease, Article, Survival outcome, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Tissue Distribution, Pharmacology (medical), Progression-free survival, Neoplasm Metastasis, Aged, Retrospective Studies, Aged, 80 and over, Pharmacology, Models, Statistical, Framingham Risk Score, business.industry, Patient Selection, Phase 1 trials, Phase i trials, Middle Aged, Prognosis, medicine.disease, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, Prognostic model, Female, Colorectal Neoplasms, business, Follow-Up Studies

الوصف: Background Patients with metastatic colorectal cancer (mCRC) who progress on standard therapies may be eligible for phase I trials. To better delineate the risk-benefit ratio, we assessed toxicities, clinical outcomes and prognostic factors. Methods Records of mCRC patients on phase I trials at our institution over 18 years were reviewed. Univariable (UVA) and multivariable analyses (MVA) were undertaken and a prognostic model developed. Results There were 187 enrollments on 37 phase I trials. Median age was: 59 (29-83) years and number of prior therapies: 3 (0-8). The clinical benefit rate (CBR): response (5.6%) + stable disease, was 43.1%. Median progression free survival (PFS) and overall survival (OS) was 7.7 weeks and 43.7 weeks, respectively. The MVA identified age 60 years (HR 1.63, p 0.004), albumin3.5 g/dL (HR 3.69, p 0.001), direct bilirubinULN (HR1.69, p 0.01), and WBC ≥ 5.2 k/uL (HR 1.97, p 0.001) as negative prognostic factors. A risk score based on the MVA revealed that patients with a score of 0-1 had an improved OS (58.7 weeks) compared to a score of 2 (49.9 weeks, p 0.01) and 3 (14.1 weeks, p 0.001). Conclusions Phase 1 trials may offer similar or better clinical outcome for mCRC patients than standard third line therapies; the prognostic model could assist in selecting appropriate patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8e7980ad2672d11c6f466b0df5b1adf3Test
https://doi.org/10.1007/s10637-018-0675-9Test

المؤلفون: Takaaki Tokito, Takashi Kojima, Hidenobu Ishii, Norikazu Matsuo, Kazuhiko Yamada, Tomoaki Hoshino, Koichi Azuma

المصدر: Investigational new drugs. 39(4)

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Lung Neoplasms, Combination therapy, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Disease, Gastroenterology, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Pharmacology (medical), Adverse effect, Lung cancer, Immune Checkpoint Inhibitors, Pneumonitis, Aged, Retrospective Studies, Pharmacology, Aged, 80 and over, Chemotherapy, business.industry, Incidence (epidemiology), Incidence, Middle Aged, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Female, business

الوصف: Immune-related adverse events (irAEs) and hyperprogressive disease (HPD) are serious problems arising in the early period of monotherapy (MT) with programmed cell death protein 1 (PD-1) and programmed cell death ligand1 (PD-L1) inhibitors. However, the frequency and clinical features of these problems in patients receiving combination therapy (CT) with cytotoxic chemotherapy in addition to these agents remain unclear. We retrospectively screened patients with pathologically confirmed advanced or recurrent non-small cell lung cancer (NSCLC) who had received PD-1/PD-L1 inhibitors at Kurume University Hospital between February 2016 and March 2020. We recruited 210 patients, of whom 172 (81.9%) had received PD-1/PD-L1 inhibitor MT and 38 (18.1%) had received CT. The incidence of irAE during the 3 months after treatment initiation was significantly higher in the MT group (57 of 172, 33.1%) than in the CT group (6 of 38, 15.8%) (p = 0.049). During the same period, the incidence of pneumonitis was also higher in the MT group (18 of 172, 10.9%) than in the CT group (0 of 38) (p = 0.049). A similar trend was observed in patients who had received these treatments on a first line basis. The HPD rate was significantly lower in the CT group (1 of 34, 2.9%) than in the MT group (25 of 142, 17.6%) (p = 0.031). The incidences of HPD and irAE, especially pneumonitis, during 3 months after treatment initiation were relatively lower in the CT group than in the MT group. The mechanisms underlying these differences warrant further study.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b33e9c0562b5d14a59198e2debd0714Test
https://pubmed.ncbi.nlm.nih.gov/33483882Test

المؤلفون: Shigehisa Kitano, Naoki Fukuda, Kenji Tamura, Makiko Ono, Kan Yonemori, Junichi Tomomatsu, Jun Sato, Noboru Yamamoto, Toshio Shimizu, Shunji Takahashi, Kazuki Sudo, Satoru Iwasa, Takafumi Koyama, Shunsuke Kondo

المصدر: Investigational New Drugs

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Maximum Tolerated Dose, Antineoplastic Agents, Ubiquitin-Activating Enzymes, Phase 1, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pharmacokinetics, Liver Function Tests, Internal medicine, Neoplasms, Phase I Studies, Solid tumors, medicine, Humans, Pharmacology (medical), Pyrroles, Dosing, Stage (cooking), Adverse effect, Aged, Pharmacology, medicine.diagnostic_test, biology, Dose-Response Relationship, Drug, business.industry, TAS4464, Middle Aged, Discontinuation, 030104 developmental biology, Pyrimidines, Treatment Outcome, Oncology, Enzyme inhibitor, 030220 oncology & carcinogenesis, NEDD8 activating enzyme E1 inhibitor, biology.protein, Female, Liver function, Chemical and Drug Induced Liver Injury, Safety, business, Liver function tests

الوصف: SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ac6ac972d01ecaf4b81ee6784d289774Test
https://pubmed.ncbi.nlm.nih.gov/33560503Test