Phase I Dose-Escalation and Pharmacokinetic Study of Intravenous Aflibercept in Combination with Docetaxel, Cisplatin, and 5-Fluorouracil in Patients with Advanced Solid Malignancies.
Oncology
; 90(1): 10-20, 2016.
Article
de En
| MEDLINE
| ID: mdl-26492090
ABSTRACT
PURPOSE:
This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. PATIENTS ANDMETHODS:
Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated.RESULTS:
Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease.CONCLUSION:
Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines de fusion recombinantes
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Protocoles de polychimiothérapie antinéoplasique
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Facteur de stimulation des colonies de granulocytes
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Récepteurs aux facteurs de croissance endothéliale vasculaire
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Facteur de croissance endothéliale vasculaire de type A
/
Tumeurs
Type d'étude:
Clinical_trials
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Guideline
Limites:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Langue:
En
Journal:
Oncology
Année:
2016
Type de document:
Article
Pays d'affiliation:
France