First Resultsfroma Phase IbStudyof theanti-EpCAMAntibody Adecatumumab (MT201) in CombinationwithDocetaxelin Patients withMetastatic BreastCancer

M. Schuler (Mainz), C. Hanusch(Munich), G.G. Steger (Vienna), M. Schmidt (Mainz), A. Lang (Feldkirch), C. Wolf (Ulm), M. Sebastian (Mainz), D. Rüttinger(Munich), M. Schmidt (Munich), C. Reinhardt (Munich), W. Eiermann(Munich)

Introduction Patients Overexpressionof the epithelial cell adhesion molecule (EpCAM) has been To date, a total of 19 patients with a median of 3 prior lines were associated with poor outcome in (Figure 1 and Ref. 1). Data from a treated with the combination of docetaxeland adecatumumab q21d. Seven patients previous phase II clinical trial in patients suffering from metastatic breast cancer were treated at dose level 1 (180mg/m2) and 12 patients at dose level 2 (MBC) suggested that single agent treatment with the anti-EpCAM antibody (550mg/m2). Overall, baseline characteristics were comparable between the adecatumumab (MT201) could mitigate this negative prognostic effect and prolong treatment groups. Prior therapies included anthracyclinesin 18 patients (95%) and progression-free survival in patients with high-level EpCAM expression2, most taxanesin 13 patients (68%), respectively (Table 1). 74% of patients had probably by inhibiting outgrowth of new metastases3.Docetaxel(Taxotere®) has previously undergone hormonal therapy, and 21% had been pre-treated with been approved for locally advanced or metastatic breast cancer. This phase Ibtrial monoclonal antibodies. was designed to test the safety and tolerability of a combination of docetaxelwith increasing doses of adecatumumab. Table 1:Patient characteristics Dose level 1 Dose level 2 low EpCAM high EpCAM (n = 7) (n = 12) (n = 10) (n = 9) Fig. 1: EpCAM Expression and Survival in Node-positive Primary BC Age [mean + SD] 59 + 14 53 + 13 57 + 12 52 + 15 Kaplan–Meier analysis of overall survival. Black line: Patients with high EpCAM expression ECOG-PS = 0/1/2 [%] 43/29/29 67/33/0 60/30/10 56/33/11 (score >4, n=383). Dotted line: patients with low EpCAM expression (score 1–4, n=395). Duration of disease [years; median] 7.4 4.6 6.2 5.0 Grey line: patients with breast cancer lacking EpCAM expression (score 0, n=75). [Taken from Spizzo et al. (2004), Breast Cancer Res Treat, 86:207] Previous chemotherapy [%] 100 100 100 100 Number of [median] 3 2.5 3 3 Previous taxane therapy [%] 71 67 70 67 Prevous anthracycline therapy [%] 100 92 90 100 Previous hormonal therapy [%] 71 75 90 56 EpCAM negative Previous monoclonal antibodies [%] 29 17 20 22

EpCAM „low“ Results Overall, the occurrence of adverse events (AE) was slightly higher in patients EpCAM „high“ receiving adecatumumab at dose level 2 (430 AE in 12 patients) as compared to patients treated at dose level 1 (211 AE in 7 patients). Specifically, a higher rate was seen for infusion-related symptoms (chills, headache) and gastrointestinal symptoms (diarrhoea, nausea, vomiting; Table 2). At dose level 2(550mg/m2), four patients experienced grade 3 diarrhoea; two patients had grade 3 diarrhoea for >24h representing dose-limiting toxicity. No evidence of aggravation of grade 3/4 toxicities typically associated with docetaxeltreatment was observed except for an increased rate of lymphocytopeniaat dose level 2.

Methods Table 2:Adverseevents(frequency>20%; irrespectiveof relationship) This study was designed as an open-label, dose-escalation study investigating the safety and tolerability of standard-dose docetaxelcombined with increasing doses of adecatumumab in patients with EpCAM-positive relapsed or primary refractory advanced stage breast cancer. Patients had to have histologicallyconfirmed EpCAM expression and at least one measurable lesion (according to RECIST). Major exclusion criteria were clinically symptomatic or progressive CNS metastases, chemotherapy within 4 weeks, treatment with any investigational product within 12 weeks prior to study entry, major lab abnormalities, and need for immunosuppressive . A maximum of four previous chemotherapy regimens was allowed. Testing for EpCAM expression was done using IHC staining of the patients´archived tumour tissue according to published methodology1. Based on the test result patients were grouped by a central pathologist into low/intermediate (“low EpCAM”) and high-level EpCAM expression (“high EpCAM”) according to their estimated staining intensity (Figure 2).

Fig. 2: Examplesof EpCAM Expression in breast cancer specimen The overall response rate (CR/PR as assessed by RECIST criteria)in all evaluable (negative, low, and high -from left to right) patients was 20%. Patients with high EpCAM-expressing tumorsshowed a As per the previously described “composite score”(Ref. 1) IHC samples exhibiting 3+ response rate of 43%, whereas no responses were detected in patients with low staining intensity on at least 10% of cells as well as patients exhibiting 2+ staining intensity on at least 50% of cells were assigned as “high”(composite score >4). All EpCAM expression. The clinical benefit rate (CBR) defined as theproportion of other samples expressing EpCAM at lower levels were assigned as “low”. patients with complete response (CR), partial response (PR) or stable disease (SD for >24 weeks) was 57% in patients with high EpCAM-expressing tumors, and 13% in patients with low EpCAM expression (Table 3). Current median time to progression (TTP) is 127 days for all patients with a trend for longer TTP in patients receiving the higher dose of adecatumumab. However, longer follow-up is needed to substantiate this observation (data not shown).

Table 3:Response assessmentaccordingto RECIST

Dose level1 Dose level2 EpCAM low EpCAM high Total (n=6) (n=9) (n=8) (n=7) (n=15) Patients were treated with standard-dose docetaxel(100mg/m2 q21d; dose Overall response(CR, PR) [n (%)] 1 (16.7) 2 (22.2) 0 3 (42.9) 3 (20.0) reduction allowed) in combination with adecatumumab q21d (dose levels tested: 180mg/m2 [dose level 1] and 550mg/m2 [dose level 2]). In order to rapidly Clinicalbenefit(CR, PR orSD>24w) [n (%)] 2 (33.3) 3 (33.3) 1 (12.5) 4 (57.1) 5 (33.3) reach steady state concentrations, an adecatumumab loading dose was administered on days 0 and 7 consisting of 100mg/m2 [dose level 1] and Conclusion 300mg/m2 [dose level 2], respectively (Figure 3). These interim results indicate that combining adecatumumab (MT201) with docetaxelis safe and feasible in patients with extensively pretreatedMBC. Next Fig. 3: Schedule of treatmentwithdocetaxeland adecatumumab to asymptomatic lymphocytopenia, gastrointestinal disorders such as diarrhoea appeared to be the main toxicity at the higher dose of adecatumumab, but were clinically well manageable in the majority of cases. The apparent ) ) difference in clinical outcome depending on EpCAM expression levels is in line loa d ing loa d ing (

( with earlier observations. Further development of adecatumumab combination ad e catu m u ab do c eta x el do c eta x el ad e catu m u ab ade c atu m um ab do c eta x el do c eta x el ade c atu m um ab ade c atu m um ab therapies in patients with tumorsexpressing high levels of EpCAM is warranted.

d0 d7 d14 d21 d42 d63 References Primary objectives were safety and tolerability of the combination treatment. 1.Spizzo et al. (2004), BreastCancer Res Treat, 86:207 2.Awadaetal. (2007), J ClinOncol, 25(18S):159 Secondary objectives included anti-tumoractivity and pharmocokinetics. 3.Dittrich et al. (2007) NCI-AACR-EORTC 2007, A71