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CLEAN supplementary material Daco+figi 1004 CCR Sesub v4.0 from A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

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posted on 2023-03-31, 18:41 authored by Emiliano Calvo, Jean-Charles Soria, Wen Wee Ma, Tao Wang, Rastilav Bahleda, Anthony W. Tolcher, Diana Gernhardt, Joseph O'Connell, Robert Millham, Nagdeep Giri, Michael J. Wick, Alex A. Adjei, Manuel Hidalgo

Supplementary material Supplementary Table 1. Customized primer panel for Sequenom MassARRAY® somatic mutation profiling of DNA from models of adenoid cystic carcinoma. Supplementary Figure 1. Apparent oral clearance (CL/F) of dacomitinib 10 mg (D-1b) and 15 mg (D-1d) in the presence of figitumumab (20 mg/kg). Boxes, 25th-75th percentiles (1st-3rd quartiles); circles individual patient values; horizontal black bars, medians; whiskers, 1.5 Ã- interquartile range. Supplementary Figure 2. Dose-normalized maximal plasma concentration (Cmax; A) and area under the concentration-time curve (AUC24; B) for dacomitinib 10 mg (D-1b) and 15 mg (D-1d) in the presence of figitumumab (20 mg/kg) (Pfizer, data on file). Boxes, 25th-75th percentiles (1st-3rd quartiles); circles individual patient values; horizontal black bars, medians; whiskers, 1.5 Ã- interquartile range. Supplementary Figure 3. Apparent oral clearance (CL/F) of dacomitinib in the presence (cohorts D-1b and D-1d in this study [study 1004]) and the absence (studies 1001, 1003, and 1005) of figitumumab (20 mg/kg) (Pfizer, data on file). Boxes, 25th-75th percentiles (1st-3rd quartiles); circles individual patient values; horizontal black bars, medians; whiskers, 1.5 Ã- interquartile range. Supplementary Figure 4. Dose-normalized maximal plasma concentration (Cmax; A) and area under the concentration-time curve (AUC24; B) for dacomitinib in the presence (cohorts D-1b and D-1d in this study [study 1004]) and the absence (studies 1001, 1003, and 1005) of figitumumab (20 mg/kg) (Pfizer, data on file). Boxes, 25th-75th percentiles (1st-3rd quartiles); circles individual patient values; horizontal black bars, medians; whiskers, 1.5 Ã- interquartile range.

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Pfizer Inc.

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ARTICLE 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 AACR.See related commentary by Sundar et al., p. 1123

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    Clinical Cancer Research

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    Clinical Trial ResultsClinical-Stage ResearchDrug TargetsPreclinical ModelsAnimal models of cancerXenograft modelsSmall Molecule AgentsTranslational Research

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