Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors
| العنوان: | Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors |
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| المؤلفون: | Elizabeth Blackwood, Jennifer O. Lauchle, Rui Zhu, Yuan Chen, Jean-Charles Soria, Srikumar Sahasranaman, Xuyang Lu, Jennifer L. Schutzman, Patricia LoRusso, Elaine Murray, Franklin Peale, Sami Mahrus, Sophie Postel-Vinay, Jeffrey R. Infante, Xiao Ding, Todd M. Bauer, Antoine Hollebecque, Marie Evangelista |
| المصدر: | Clinical Cancer Research. 23:2423-2432 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Nausea, medicine.medical_treatment, Triple Negative Breast Neoplasms, Pharmacology, Neutropenia, Deoxycytidine, Gastroenterology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Piperidines, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Melanoma, Aged, Chemotherapy, Dose-Response Relationship, Drug, business.industry, Cancer, Middle Aged, medicine.disease, Gemcitabine, 030104 developmental biology, Oncology, Tolerability, Bone marrow suppression, 030220 oncology & carcinogenesis, Checkpoint Kinase 1, Vomiting, Female, medicine.symptom, business, Heterocyclic Compounds, 3-Ring, medicine.drug |
| الوصف: | Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors. Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1,000 mg/m2 (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses. Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2. Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin. Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423–32. ©2016 AACR. |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e8c5bc855dc1b1a96d7edd9072a8b2c0Test https://doi.org/10.1158/1078-0432.ccr-16-1782Test |
| رقم الانضمام: | edsair.doi.dedup.....e8c5bc855dc1b1a96d7edd9072a8b2c0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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