Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors
| Autor: | Elizabeth Blackwood, Antoine Hollebecque, Kelly DuPree, Xuyang Lu, Sami Mahrus, Sophie Postel-Vinay, Jennifer L. Schutzman, Elaine Murray, Erika Hamilton, Sara M. Tolaney, A. Moein, Michael Tagen, J. R. Infante, Antoine Italiano, J. Epler, Kathleen N. Moore, Maud Toulmonde, Jean-Charles Soria, Jennifer O. Lauchle, Geoffrey I. Shapiro, Patricia LoRusso, Franklin Peale, Sophie Cousin |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Oncology medicine.medical_specialty Neutropenia Cell cycle checkpoint Maximum Tolerated Dose Pyridines Deoxycytidine 03 medical and health sciences 0302 clinical medicine Piperidines Pharmacokinetics Neoplasms Internal medicine Antineoplastic Combined Chemotherapy Protocols Humans Medicine Drug Interactions Pyrroles CHEK1 Adverse effect Protein Kinase Inhibitors Fatigue Aged Aged 80 and over Dose-Response Relationship Drug business.industry Nausea Hematology Middle Aged medicine.disease Thrombocytopenia Gemcitabine Treatment Outcome 030104 developmental biology Tolerability 030220 oncology & carcinogenesis Pharmacodynamics Checkpoint Kinase 1 Female business Half-Life medicine.drug |
| Zdroj: | Annals of Oncology. 29:1304-1311 |
| ISSN: | 0923-7534 |
| Popis: | Background Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. Patients and methods In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000mg/m2 (arm 2a) or 500mg/m2 (arm 2b), followed by GDC-0575 (45 or 80mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. Results Of 102 patients treated, 70% were female, the median age was 59years (range 27–85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2hours of dosing, and half-life was ∼23hours. No pharmacokinetic drug–drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. Conclusion GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. Clinical trial number NCT01564251. |
| Databáze: | OpenAIRE |
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