title: A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors.
abstract: 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 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.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 five 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 every 3 weeks 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 adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug-drug interaction. In the adenoid cystic carcinoma xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed downregulation 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 adenoid cystic carcinoma.Clin Cancer Res; 23(5); 1177-85. ©2016 AACRSee related commentary by Sundar et al., p. 1123.
authors.affiliation: START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain. emiliano.calvo@start.stoh.com.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Institut Gustave Roussy, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.affiliation: Pfizer Inc., Groton, Connecticut.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institut Gustave Roussy, Paris, France.
authors.forename: Rastilav
authors.initials: R
authors.lastname: Bahleda
authors.affiliation: START, San Antonio, Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Pfizer Inc., Groton, Connecticut.
authors.forename: Diana
authors.initials: D
authors.lastname: Gernhardt
authors.affiliation: Pfizer Inc., New York, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Connell
authors.affiliation: Pfizer Inc., Groton, Connecticut.
authors.forename: Robert
authors.initials: R
authors.lastname: Millham
authors.affiliation: Pfizer Inc., La Jolla, California.
authors.forename: Nagdeep
authors.initials: N
authors.lastname: Giri
authors.affiliation: START, San Antonio, Texas.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wick
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.affiliation: START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D052999:Quinazolinones / Q000008:administration & dosage* / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D052999:Quinazolinones; C525726:dacomitinib; C525021:figitumumab