A Phase I Clinical Trial and Independent Patient-derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors
Mené sur 74 patients atteints d'une tumeur solide de stade avancé, puis complété par une étude sur des modèles murins de carcinome adénoïde kystique avec xénogreffes de tumeurs dérivées des patients, cet essai de phase I évalue les caractéristiques pharmacocinétiques et l'efficacité, du point de vue du taux de réponse objective, et la toxicité d'un traitement combinant dacomitinib et figitumumab
Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib−figitumumab combination therapy in patients with advanced solid tumors. Experimental Design: A standard 3+3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks (q3w) and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma (ACC). Results: Of the 74 patients enrolled, the most common malignancies were non-small cell lung cancer (24.3%) and colorectal cancer (14.9%). The most common treatment-related adverse events in the 71 patients who received treatment across 5 dose levels were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg q3w after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with ACC, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug−drug interaction. In the ACC xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed down-regulation of genes in the insulin-like growth factor-receptor-1 pathway. Conclusions: Dacomitinib−figitumumab combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug. Preliminary clinical activity was demonstrated in the potential target tumor ACC. http://clincancerres.aacrjournals.org/content/clincanres/early/2016/10/12/1078-0432.CCR-15-2301.full.pdf