CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector ORIGINAL ARTICLE A Phase I/II Study of Erlotinib in Combination with the Anti-Insulin-Like Growth Factor-1 Receptor Monoclonal Antibody IMC-A12 (Cixutumumab) in Patients with Advanced Non-small Cell Lung Cancer Andrew Weickhardt, MBBS, DMedSc,* Robert Doebele, MD, PhD,* Ana Oton, MD,* Janice Lettieri, BSN,* DeLee Maxson, BS,* Michele Reynolds, BS,* Amy Brown, PhD,* Mary K. Jackson, AD,* Grace Dy, MD,† Araba Adjei, PhD,† Gerald Fetterly, PhD,† Xian Lu, MSc,‡ Wilbur Franklin, MD,* Marileila Varella-Garcia, PhD,* Fred R. Hirsch, MD, PhD,* Murry W. Wynes, PhD,* Hagop Youssoufian, MD,§ Alex Adjei, MD, PhD,† and D. Ross Camidge, MD, PhD* growth factor-1 levels as seen with other insulin-like growth fac- Introduction: This phase I/II study evaluated the safety and anti- tor-1R inhibitors. tumor effect of the combination of erlotinib with cixutumumab, a Conclusions: The combinations of cixutumumab at 6 mg/kg every recombinant fully humanized anti-insulin-like growth factor-1 re- 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not ceptor IgG1 monoclonal antibody, in advanced non-small cell lung tolerable in unselected patients with NSCLC, as measured by DLT. cancer (NSCLC). Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but Methods: Patients with advanced NSCLC were treated in an initial dose delays were common. Efficacy in unselected patients with safety-lead and drop-down cohorts using erlotinib 150 mg/d with NSCLC seems to be low. cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an addi- Key Words: Non-small cell lung cancer, IGF1R monoclonal anti- tional cohort (3 ϩ 3 design) with cixutumumab at 15 mg/kg on day body, EGFR, Metastatic disease. 1 in 21-day cycles (cohort 3). (J Thorac Oncol. 2012;7: 419–426) Results: Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), ung cancer causes more than 150,000 deaths annually in whereas at 5 mg/kg, one of eight patients experienced DLT but three Lthe United States.1 Epidermal growth factor receptor ty- of eight patients still required a dose delay during cycle 1. At 15 rosine kinase inhibitors (EGFR-TKIs) produce responses in mg/kg every 21 days, two of four patients experienced DLTs. In all patients with non-small cell lung cancer (NSCLC) with cohorts, DLTs were either G3 rash or fatigue. Five patients had EGFR-activating mutations; however, all responders eventu- stable disease as best response and 14 patients had progressive ally develop resistance, most commonly because of the emer- disease. The median progression-free survival was 39 days (range gence of a secondary T790M mutation or mesenchymal-epithe- 21–432ϩ days). Biomarkers analyses showed a trend toward better lial transition factor (cMET) amplification.2–4 Responses in progression-free survival seen with higher free baseline insulin-like EGFR wild-type (EGFR-WT) patients also occur but are rare.5 EGFR-TKIs in unselected patients produce improvements in the second- and third-line setting in progression-free survival (PFS) *University of Colorado Cancer Center, Aurora, Colorado; †Roswell Park and overall survival (OS) compared with placebo, although the Cancer Institute, Buffalo, New York; ‡Department of Biostatistics and gains are modest.6 Informatics, Colorado School of Public Health and University of Colo- rado, Aurora, Colorado; and §Imclone, Bridgewater, New Jersey. In vitro and in vivo studies have implicated the insulin- Disclosure: Dr. Andrew Weickhardt and Dr. D. Ross Camidge have received like growth factor receptor (IGF-1R), its ligands IGF I and II, honorarium from Pfizer in the previous 12 months. No other authors have and its related downstream signaling in the development and relevant affiliations or financial involvement with any organization or progression of cancer.7 Furthermore, the IGF-1R pathway is entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article. implicated as an alternate possible cause of acquired resis- Address for correspondence: Andrew Weickhardt, MBBS, DMedSc, Uni- tance to EGFR-targeted therapy.8,9 Preclinical work demon- versity of Colorado Cancer Center, Aurora, CO 80045. E-mail: strates that the combination of an IGF-1R inhibitor with an [email protected] EGFR-TKI is synergistic in both NSCLC cancer cell lines Copyright © 2012 by the International Association for the Study of Lung Cancer that are EGFR-WT and those with mutations in EGFR exons ISSN: 1556-0864/12/0702-0419 19 and 21 (EGFR mutation [MT]).10–15 Journal of Thoracic Oncology • Volume 7, Number 2, February 2012 419 Weickhardt et al. Journal of Thoracic Oncology • Volume 7, Number 2, February 2012 FIGURE 1. Dose cohorts in the phase I trial. Cixutumumab (previously IMC-A12; Imclone; Bridge- hematopoietic, hepatic, and renal function. Exclusion criteria water, NJ) is a fully humanized recombinant IgG1/␭ mono- included previous exposure to other EGFR or IGF-1R inhib- clonal antibody with high affinity to the extracellular domain itors; chemotherapy within five half-lives of the agent or 28 of IGF-1R with a mean effective concentration of 0.04 days if the half-life was unknown or was a monoclonal nmol/liter, acting as an antagonist of the IGF-I and IGF-II antibody; radiotherapy within 28 days; major surgery within ligand binding.16 In vitro, cixutumumab treatment induced 4 months of the study; ongoing previous treatment-related apoptosis in sensitive human tumor cell lines and elicited side effects/AEs that were Նgrade 2; known brain metastases both tumor growth inhibition and tumor regression across a unless adequately treated and stable off anticonvulsants and broad range of human tumor xenograft models.16 In combi- steroids; pregnancy; and poorly controlled diabetes mellitus nation with EGFR-TKI therapy, cixutumumab showed in- or other uncontrolled intercurrent illness. creased cytoxicity compared with either agent alone in cell The protocol was approved and monitored by all local lines and in xenografts.16 institutional review boards. All patients provided written Cixutumumab monotherapy, administered intravenously consent before enrollment. (IV) every 7 days, is tolerated at doses of up to 10 mg/kg.17 In a phase II trial of 10 mg/kg of IV cixutumumab every 7 Study Design and Drug Dosing and days in pretreated patients with chemotherapy refractory Administration advanced colon cancer, there were few grades 3 and 4 side Patients were enrolled at two institutions into one of the effects attributable to the drug, with asymptomatic hypergly- three cohorts (Figure 1). To assess safety and tolerability, the cemia the most frequent drug-related adverse event (AE).17 initial safety-lead and drop-down cohort used erlotinib 150 The mean terminal elimination half-life of cixutumumab is mg orally daily with cixutumumab 6 mg/kg (cohort 1) or 5 148 hours, with trough concentrations above those shown mg/kg (cohort 2) IV on days 1, 8, 15, and 22 in 28-day cycles. effective in xenograft models (data on file, Imclone). In a Tolerability required the completion of one cycle in 8 of 10 subsequent phase I study, cixutumumab was shown to be patients without dose-limiting toxicity (DLT). Emerging tolerable up to and including 20 mg/kg when given every 21 pharmacokinetic data related to 21-day dosing of cixutu- days, although these data were not available until midway mumab led to an amendment and enrollment of a third cohort through accrual for this clinical trial (data on file, Imclone). with erlotinib 150 mg orally daily with cixutumumab 15 The primary objectives of this study were to explore the mg/kg IV in 21-day cycles (cohort 3). In this cohort, for safety and efficacy of the combination of cixutumumab with toxicity and feasibility assessment, a standard 3 ϩ 3 phase I full-dose erlotinib, before planned expansion into a random- design was used. At least three patients were required to have ized phase II study comparing full-dose erlotinib with the completed one cycle for dose escalation to occur to a planned combination. cohort 4 (cixutumumab 20 mg/kg IV in 21-day cycles). If there was one DLT among the first three patients, an addi- PATIENTS AND METHODS tional three patients were enrolled at the same dose level. If two DLTs were observed in up to six patients, then dosing at Patient Selection that level was stopped. The highest tolerated dose regimen Patients with histologically or cytologically docu- was to be declared the maximum tolerated dose (MTD). mented locally advanced or metastatic NSCLC, age older DLT was defined as any treatment delay of Ն7 days than or equal to 18 years, and those who had progressed on or because of any drug-related toxicity within cycle 1, or any after receiving platinum-containing chemotherapy were eli- nonhematological toxicity Նgrade 3 within cycle 1, exclud- gible. A later amendment allowed the enrollment of patients ing rash, diarrhea, nausea, hyperglycemia, hypocalcemia, with EGFR-MTs who were untreated. Other criteria included hypokalemia, hypomagnesemia, hyponatremia, hypophos- Eastern Cooperative Oncology Group performance status phatemia, or hypercholesterolemia if controllable within 7 Յ2; life expectancy Ն3 months; presence of evaluable or days of holding drug, and no dose reductions occurred. For measurable