Phase I Dose-Escalation Trial of Checkpoint Kinase 1 Inhibitor MK-8776 As Monotherapy and in Combination With Gemcitabine in Patients With Advanced Solid Tumors
| Autor: | Adil Daud, Randi Isaacs, Jonathan W. Goldman, Lee S. Rosen, Frances Shanahan, Jennifer A. Grabowsky, Tomoko Freshwater, Alan P. Venook, David S. Mendelson, Stuart Shumway, Sabine Loechner, Christopher Sorge, David Parry, Pamela N. Munster, Soonmo Peter Kang, Gregory M. Springett, Jonathan Strosberg, Michelle T. Ashworth |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Time Factors Combination therapy Nausea Phases of clinical research Antineoplastic Agents Adenocarcinoma Pharmacology Deoxycytidine Gastroenterology Cohort Studies Histones Pharmacokinetics Neoplasms Internal medicine Humans Medicine Infusions Intravenous Adverse effect Melanoma Protein Kinase Inhibitors Aged Aged 80 and over business.industry Cytarabine Sarcoma Middle Aged Gemcitabine Clinical trial Pyrimidines Oncology Pharmacodynamics Checkpoint Kinase 1 Pyrazoles Female medicine.symptom K562 Cells business Protein Kinases medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 33:1060-1066 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2014.57.5027 |
| Popis: | Purpose We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies. Patients and Methods Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m2 as monotherapy and then in combination with gemcitabine 800 mg/m2 (part A, n = 26) or gemcitabine 1,000 mg/m2 (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine. Results As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease. Conclusion MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m2 on days 1 and 8 of a 21-day cycle. |
| Databáze: | OpenAIRE |
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