Didier Meulendijks1,2,3, Jan Willem B de Groot4, Maartje Los5, James E Boers6, Laurens V Beerepoot7, Marco B Polee8, Aart Beeker9, Johanna E A Portielje10, Swan H Goey11, Robert S de Jong12, Steven A L W Vanhoutvin3, Maria Kuiper3, Karolina Sikorska13, Dick Pluim2, Jos H Beijnen14,15, Jan H M Schellens1,2,15, Cecile Grootscholten3,16, Margot E T Tesselaar16, Annemieke Cats3. 1. Division of Medical Oncology, Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 2. Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 3. Division of Medical Oncology, Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 4. Department of Medical Oncology, Isala, Zwolle, The Netherlands. 5. Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands. 6. Department of Pathology, Isala, Zwolle, The Netherlands. 7. Department of Oncology, St. Elisabeth Hospital, Tilburg, The Netherlands. 8. Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands. 9. Department of Internal Medicine, Spaarne Hospital, Hoofddorp, The Netherlands. 10. Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands. 11. Department of Internal Medicine, Tweesteden Hospital, Tilburg, The Netherlands. 12. Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands. 13. Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. 14. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 15. Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. 16. Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract
BACKGROUND: The current study was a multicenter, single-arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, previously untreated, gastric or gastroesophageal adenocarcinoma. METHODS: Tumor HER2 status was determined centrally. Patients received 6 cycles of bevacizumab at a dose of 7.5 mg/kg, docetaxel at a dose of 50 mg/m(2) , and oxaliplatin at a dose of 100 mg/m(2) (all on day 1) combined with capecitabine at a dose of 850 mg/m(2) twice daily (days 1-14) every 3 weeks followed by maintenance with capecitabine and bevacizumab in patients with disease control. The primary objective was to demonstrate a progression-free survival (PFS) of >6.5 months, according to the 95% confidence interval (95% CI). Secondary endpoints included safety, objective response rate, overall survival (OS), analyses of circulating tumor cells (CTCs), and pharmacogenetic analyses. RESULTS: Sixty eligible patients were enrolled. The median PFS was 8.3 months (95% CI, 7.2-10.9 months). The objective response rate was 70% (95% CI, 55%-83%) and the disease control rate was 96% (95% CI, 85%-99%). The median OS was 12.0 months (95% CI, 10.2-16.1 months). According to CTC-AE v4.0, the most common treatment-related grade ≥3 adverse events were neutropenia (20%), leukocytopenia (18%), diarrhea (15%), and nausea/vomiting (15%). The presence of CTCs at baseline was strongly predictive of PFS (hazard ratio [HR], 3.8; P =.007) and OS (HR, 3.4; P =.014). The methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype was strongly associated with PFS (HR, 4.7 for TT vs CC or CT; P =.0007) and OS (HR, 5.9; P =.0001). CONCLUSIONS: The B-DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B-DOC. Docetaxel-based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016;122:1434-1443.
BACKGROUND: The current study was a multicenter, single-arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOC) in patients with advanced humanepidermal growth factor receptor 2 (HER2)-negative, previously untreated, gastric or gastroesophageal adenocarcinoma. METHODS:TumorHER2 status was determined centrally. Patients received 6 cycles of bevacizumab at a dose of 7.5 mg/kg, docetaxel at a dose of 50 mg/m(2) , and oxaliplatin at a dose of 100 mg/m(2) (all on day 1) combined with capecitabine at a dose of 850 mg/m(2) twice daily (days 1-14) every 3 weeks followed by maintenance with capecitabine and bevacizumab in patients with disease control. The primary objective was to demonstrate a progression-free survival (PFS) of >6.5 months, according to the 95% confidence interval (95% CI). Secondary endpoints included safety, objective response rate, overall survival (OS), analyses of circulating tumor cells (CTCs), and pharmacogenetic analyses. RESULTS: Sixty eligible patients were enrolled. The median PFS was 8.3 months (95% CI, 7.2-10.9 months). The objective response rate was 70% (95% CI, 55%-83%) and the disease control rate was 96% (95% CI, 85%-99%). The median OS was 12.0 months (95% CI, 10.2-16.1 months). According to CTC-AE v4.0, the most common treatment-related grade ≥3 adverse events were neutropenia (20%), leukocytopenia (18%), diarrhea (15%), and nausea/vomiting (15%). The presence of CTCs at baseline was strongly predictive of PFS (hazard ratio [HR], 3.8; P =.007) and OS (HR, 3.4; P =.014). The methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype was strongly associated with PFS (HR, 4.7 for TT vs CC or CT; P =.0007) and OS (HR, 5.9; P =.0001). CONCLUSIONS: The B-DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B-DOC. Docetaxel-based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016;122:1434-1443.
Authors: D Meulendijks; E A Rozeman; A Cats; K Sikorska; M Joerger; M J Deenen; J H Beijnen; J H M Schellens Journal: Pharmacogenomics J Date: 2016-12-20 Impact factor: 3.550
Authors: A Viúdez; A Carmona-Bayonas; J Gallego; A Lacalle; R Hernández; J M Cano; I Macías; A Custodio; E Martínez de Castro; A Sánchez; L Iglesia; P Reguera; L Visa; A Azkarate; M Sánchez-Cánovas; M Mangas; M L Limón; A Martínez-Torrón; E Asensio; A Ramchandani; A Martín-Carnicero; A Hurtado; P Cerdà; M Garrido; R Sánchez-Bayonas; R Serrano; P Jiménez-Fonseca Journal: Clin Transl Oncol Date: 2019-08-05 Impact factor: 3.405