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Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 175-184 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.114 Phase I Study of the Humanized Antiepidermal Growth Factor Receptor Monoclonal Antibody EMD72000 in Patients With Advanced Solid Tumors That Express the Epidermal Growth Factor ReceptorFrom the Department of Internal Medicine (Cancer Research), West German Cancer Center, and the Department of Pathology, University of Essen Medical School, Essen; Merck KGaA, Darmstadt, Germany; and the Laboratory of Oncology Research, Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain. Address reprint requests to Udo Vanhoefer, MD, PhD, Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Hufelandstr 55, 45122 Essen, Germany; e-mail: udo.vanhoefer{at}uni-essen.de
PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.
The epidermal growth factor receptor (EGFR; HER1/erbB-1) has recently been identified as a target for cancer therapy [1-6]. On endogenous ligand binding, EGFR activation occurs, with receptor homo- or heterodimerization and autophosphorylation of the intracellular tyrosine kinase domain [7,8]. Subsequently, a complex network of signal transduction pathways is induced, which plays a key role in regulating cell proliferation, differentiation, motility, invasion, and angiogenesis [8-11]. EGFR is expressed in a variety of human malignancies (eg, head and neck, colon, and lung cancer) and may predict poor patient prognosis and resistance to treatment in many tumor entities [11-14]. Current approaches to inhibit EGFR signaling focus on monoclonal antibodies (mAbs) directed against the receptor ectodomain (eg, chimeric immunoglobulin [Ig] G1 mAb cetuximab, humanized Ig G1 mAb EMD72000, and human IgG2 mAb ABX-EGF) or intracellularly acting low–molecular weight EGFR tyrosine kinase inhibitors (eg, gefitinib, erlotinib, EKB-569, GW572016, and CI-1033) [15-22]. Both strategies influence downstream effector molecules and may thereby alter the biology of EGFR-expressing cancer cells [23-25]. Clinical studies of mAb cetuximab either alone or in combination with cytotoxic agents demonstrated efficacy in patients with chemotherapy-refractory head and neck or colorectal cancer [26-29]. In patients with irinotecan-refractory advanced colorectal cancer, treatment with cetuximab either as a single agent or in combination with irinotecan resulted in overall remission rates of 10.8% (95% CI, 5.7% to 18.1%) and 22.9% (95% CI, 17.5% to 29.1%), respectively [29]. Similar results have been reported for patients with platinum-refractory head and neck cancer or non–small-cell lung cancer with cetuximab in combination with chemotherapy [30-32]. Single-agent cetuximab showed a favorable toxicity profile, with acneiform skin rash, asthenia, and allergic reactions being the main side effects [28,33]. Besides cetuximab, the fully human mAb ABX-EGF has entered clinical evaluation, with responses being reported in renal cancer and refractory colon cancer at weekly doses of 1.0 mg/kg to 2.0 mg/kg [15,34,35]. Side effects attributable to ABX-EGF were comparable to those of other EGFR-targeting agents and included acneiform skin rash, fatigue, diarrhea, and abdominal pain. EMD72000 is a genetically engineered humanized mAb that consists of human IgG1 heavy and light chains with some remaining murine amino acids within the complementarity-determining regions [36]. EMD72000 binds to EGFR with high specificity and affinity (KD = 3.4 x 10-10 M binding affinity for EMD72000-related cDNA sequence); EMD72000 thereby competitively blocks natural ligand binding and abrogates receptor-mediated downstream signaling. Antitumor activity of EMD72000, either alone or in combination with gemcitabine, has been observed in preclinical studies using human tumor xenografts [37,38]. Here, we report the results of a phase I dose-escalation and pharmacokinetic study of EMD72000 in patients with advanced solid tumors that express EGFR.
Eligibility requirements included age  18 years, patients with measurable metastatic or advanced solid malignancies who were not amenable to any established standard treatment, EGFR expression in tumor tissue (as defined in Patients and Methods, under EGFR Expression), predicted life expectancy 2 months, Karnofsky performance status 60%, no chemo- or radiotherapy within 4 weeks before the first infusion of EMD72000, adequate baseline organ functions, no severe uncontrolled comorbidities, and signed informed consent. The trial was initiated after the approval of the institutional ethic committee review board in November 2000. The study followed the Declaration of Helsinki and good clinical practice guidelines.
EGFR Expression
Pretreatment Evaluation and Follow-Up
Administration and Dose-Escalation Plan
Evaluation of Toxicities and Response Toxicities were evaluated weekly and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC; version 2.0). Assessment of DLTs was limited to the first 4 weeks of treatment, and DLT was defined as follows: nonhematologic toxicities exceeding grade 2 (with the exception of alopecia, nausea, vomiting, and skin reactions); NCI-CTC grade 4 vomiting and skin reactions; neutropenia grade 4 or grade 3 associated with complications (eg, neutropenic fever); thrombocytopenia NCI-CTC grade 3 or more; and toxicity-related discontinuation of treatment for more than 1 week. Tumor response was assessed by CT scans of the target lesion(s) every 8 weeks and defined according to standard WHO criteria.
Pharmacokinetics
The pharmacokinetic parameters of EMD72000 in weeks 1 and 4 were calculated according to noncompartmental methods using the pharmacokinetic software program Kinetica, version 4.0 (InnaPhase Corp, Philadelphia, PA). The following parameters were determined from the serum concentration data of EMD72000: maximum serum concentration (Cmax), time to reach Cmax (tmax), elimination rate constant ( Concentrations below the lower limit of quantification, which are before the last quantifiable data point, have been taken as zero for calculating the AUC. Pharmacokinetic results were presented only descriptively; no statistical tests were performed with pharmacokinetic parameters. For analysis of dose linearity, the AUC was divided by dose, and results were presented graphically.
Pharmacodynamics
From November 2000, to November 2001, 44 patients entered this study at the West German Cancer Center, University of Essen Medical School, Essen, Germany. Immunohistochemical analysis of EGFR expression on tumor tissue was positive in 26 patients (59%) and negative in 16 patients (36%). Paraffin slides of two patients were not assessable. Twenty-two of 26 EGFR-positive patients received EMD72000 at five different DLs (Table 1). Four patients with EGFR-positive tumors showed a rapid tumor progression during the baseline evaluation and, thereby, failed to fulfill the inclusion criteria for study treatment with EMD72000. The characteristics of the treated patients are listed in Table 2.
Twelve patients were treated at DLs 1 to 3 (Table 1), with no DLT being observed. Thus, the study was extended to DLs 4 and 5 (study amendment 1). With the dose escalation of EMD72000 to 2,000 mg/wk (DL 5), DLT occurred in two of three patients after the first infusion of EMD72000, indicating that the MTD was exceeded. DLTs consisted of headache NCI-CTC grade 3 and headache and fever grade 3 in one patient each; in addition, the third patient on this DL experienced fever NCI-CTC grade 1. These toxicities were completely reversible by symptomatic treatment (analgesics and antipyretics) within 24 hours, and all three patients continued therapy at the next lower DL (1,600 mg/wk, DL 4) in the following week without showing further severe toxicity. On the basis of these data, four additional patients entered DL 4 (EMD72000, 1,600 mg/wk); no more DLTs were observed. Thus, DL 4 with 1,600 mg/wk was defined as the MTD based on a total of 10 enrolled patients. A total of 346 weekly infusions of EMD72000, with a median number of 10 per patient (range, four to 78 infusions), were administered. The most frequent EMD72000-related adverse event after multiple administrations was skin toxicity (Table 3), including acneiform rash NCI-CTC grade 1 and 2 in 11 (50%) and three patients (14%) or epidermolysis grade 1 and 2 in six (27%) and one patient, respectively. Inflammation of the nail bed has been observed in four patients (18%). One patient experienced conjunctivitis-induced keratorhexis after multiple administrations of EMD72000 at DL 3 (1,200 mg), which resolved within 1 week after symptomatic treatment. Other nonhematologic toxicities were mild and comprised headache or fever. No hematologic side effects and no anaphylactoid reactions were observed. Four patients experienced non–drug-related grade 3 infections (two patients required antibiotics and two underwent surgery).
Twenty-two patients were assessable for pharmacokinetic analyses after the first infusion of EMD72000, and the results are listed in Table 4. Peak serum concentrations were generally achieved within 1 to 4 hours after start of infusion (Fig 1). Mean values for Cmax for weekly doses between 400 and 2,000 mg ranged between 125 and 659 µg/mL and 259 and 878 µg/mL in weeks 1 and 4, respectively. The range of mean AUC  ( = 168 hours) was 10,414 to 61,635 µg/mL * h and 27,058 to 89,263 µg/mL * h. The increase of Cmax and AUC was dose proportional, indicating linear pharmacokinetics within the tested dose range (Fig 2). The terminal t1/2 was not constant for the five dose groups. No trend toward an increase or decrease with higher doses was observed. Slightly higher values for t1/2 were found in week 4 compared with week 1 (Table 4). The sampling period (168 hours) was short in relation to the observed t1/2 (94 to 253 hours), and accordingly, the extrapolated part of the AUC0- always exceeded 20%. Accumulation ratios, given by the ratio of week 1 and week 4 data, ranged from 1.34 to 2.11 for Cmax and from 1.84 to 2.23 for AUC after repeated dosing. The mean values for Vz and Vss were found to be small and dose independent (Table 4). Pharmacokinetic parameters have been corrected to dose per kilogram for body weight and to dose per square meter for body-surface area. There was no evidence that either body weight or body-surface area altered pharmacokinetic parameters (data not shown). The incidence of DLTs did not correlate with Cmax or AUC. Cmax or AUC values observed in week 4 of treatment were approximately one and a half- to two-fold higher than in week 1, but no grade 3 headache or fever was observed after the first week of treatment.
For pharmacodynamic studies, paired pre- and on-treatment skin biopsies were obtained. Hematoxylin and eosin examination of epidermis revealed that treatment with EMD72000 caused a thinness of the stratum corneum with loss of its basket-wave configuration. Total EGFR protein was strongly expressed in the population of proliferating keratinocytes (Fig 3). Whereas EGFR phosphorylation was completely inhibited in basal keratinocytes of the epidermis after administration of EMD72000, total EGFR expression in interfollicular epidermis was not altered; likewise, TGF-  expression remained unchanged after treatment with EMD72000. Activated MAPK (pMAPK) was seen in the nuclei of basal keratinocytes and parabasal cells. After EMD72000 administration, there was a marked reduction of activated MAPK in the basal layer of the epidermis. Baseline Ki-67 expression of epidermal cells decreased after treatment with EMD72000, indicating that cell proliferation of EGFR-expressing keratinocytes was significantly inhibited. Treatment with EMD72000 resulted in increased p27kip1 staining of keratinocytes preferentially in the basal epidermal layers, and pSTAT3 was detected in the basal and suprabasal layers of the epidermis. The pharmacodynamic investigations were amended to the study protocol, and available skin biopsies were limited to doses ranging from 800 mg to 1,600 mg of EMD72000. Exceptionally, one skin biopsy was obtained from a patient at DL 1 (400 mg/wk) after 5 months of treatment. There were no differences in the pharmacodynamic effects for doses between 800 mg and 1,600 mg of EMD72000 (data not shown). Taken together, these data suggest that EMD72000 at the investigated doses significantly abrogated EGFR downstream signaling (Fig 4).
Although tumor response was not a primary end point of this study, all patients received at least four weekly administrations of EMD72000 and were assessable for efficacy. Five of 22 patients achieved a partial response, resulting in an overall response rate of 23% (95% CI, 8% to 45%). Two of 11 patients with colorectal cancer, two of four patients with head and neck cancer, and one of two patients with esophageal cancer showed a partial response (Table 5). An additional six patients (27%; 95% CI, 11% to 50%) showed a stabilization of their formerly progressive disease, including one patient with a minor response. Duration of disease stabilization was between 3 and 6 months in these patients. It is important to note that all patients were heavily pretreated and displayed progressive disease before EMD72000 administration.
This phase I trial demonstrated that the weekly administration of EMD72000 was well tolerated in doses of up to 1,600 mg/wk. The MTD of EMD72000 was exceeded at 2,000 mg, with NCI-CTC grade 3 headache and fever being dose limiting. Headache and fever resolved within 24 hours with the use of analgesics and antipyretics and was not a concern at doses below 2,000 mg. No other severe toxicities, no grade 4 toxicity, and especially no allergic reactions or severe diarrhea were observed. The most common drug-related side effect was a mild acneiform rash of NCI-CTC grade 1 in 50% and grade 2 in 14% of patients. Acneiform skin rash, occasionally severe, has been reported as the most common toxicity of treatment with both anti-EGFR antibodies (eg, cetuximab and ABX-EGF) and with low–molecular weight EGFR tyrosine kinase inhibitors (eg, gefitinib and erlotinib), suggesting a similar EGFR-related mechanism of epithelial damage [33,40]. However, the pathophysiologic basis is poorly understood because, as shown in a study with gefitinib [23], there is no clear correlation of severity of skin toxicity with the degree of EGFR inhibition.
Pharmacokinetic analyses showed that increases in Cmax and AUC were dose proportional for EMD72000 over the range of 400 mg/wk to 2,000 mg/wk, with evidence of accumulation with weekly dosing. It is noteworthy that the occurrence of DLTs did not clearly correlate with Cmax or AUC. Although Cmax and AUC were approximately two-fold higher by week 4 in patients receiving weekly doses of 1,600 mg/wk compared with the single administration of 2,000 mg/wk, no additional episodes of grade 3 headache or fever were observed. The t1/2 of EMD72000 may be underestimated in this study. The ratio of the sampling period to the calculated t1/2 was small, which may impact model-independent calculations of pharmacokinetic parameters. This conclusion is underlined by recent experiences with trastuzumab [41]. An initially calculated trastuzumab t1/2 of about 5.8 days was corrected to 28.5 days, based on a population pharmacokinetic analysis. Therefore, parameters obtained from the terminal slope of the serum concentration curve of EMD72000 (eg, t1/2 and AUC0-
For pharmacodynamic studies, serial skin biopsies were collected before and on treatment with EMD72000. As expected, total EGFR protein and TGF- Although tumor response was not a primary end point of this study, the overall response rate of 23% and an overall disease control rate of 50% indicate activity of single-agent EMD72000. Importantly, all patients were heavily pretreated and progressed before treatment with EMD72000. One patient with head and neck cancer remained on EMD72000 for 18 months with no evidence of accumulated toxicity. Recently, a lack of correlation between EGFR receptor expression and efficacy has been reported for cetuximab in patients with EGFR-expressing metastatic colorectal cancer [29]. In the present trial, no correlation between the degree of EGFR expression and tumor response to EMD72000 has been detected. Furthermore, no clear dose-response relationship was observed, and pharmacodynamic data on lower doses of EMD72000 (eg, 800 mg) showed similar inhibition of EGFR-inducible proteins. These data suggest that sufficient inhibition of the EGFR effector network is achieved at doses of EMD72000 that are well below the MTD. Other ongoing studies with EMD72000 (including positron emission tomography-CT imaging and serial tumor biopsies) are addressing pharmacodynamic end points in an effort to define the optimal biologically effective dose and schedule of EMD72000.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Udo Vanhoefer, Merck. Performed contract work within the last 2 years: Joachim Tillner, Merck; Andreas Kovar, Merck; Oliver Rosen, Merck; and Andreas Harstrick, Merck. Received more than $2,000 a year from a company for either of the last 2 years: Udo Vanhoefer, Merck.
Supported in part by a grant from Merck KGaA, Darmstadt. Presented in part at the Thirty-Eighth Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
z), elimination half-life (t1/2), area under the serum concentration-versus-time curve within one dosing interval (AUC
