1. EMR 62 202-045 Optimal dose of cetuximab given every 2 weeks (q2w): a phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (q1w) and q2w schedules in patients (pts) with metastatic colorectal cancer (mCRC) J. Tabernero, A. Cervantes, E. Martinelli, E. Vega-Villegas, F. Rojo, A. Pérez- Fidalgo, E. Casado, F. Giardiello, A. Zubel, J. Baselga Vall d’Hebron University Hospital, Barcelona, Spain; Hospital Clínico Universitario, Valencia, Spain; Second University, Naples, Italy; Hospital Universitario Marques de Valdecilla, Santander; Spain; Merck KGaA, Darmstadt, Germany

2. Background Cetuximab mean t 1/2 values increase as the dose of cetuximab increases from 20 mg/m 2 to 200 mg/m 2 At the recommended dosing regimen of a 400 mg/m 2 initial dose followed by 250 mg/m 2 weekly, mean t 1/2 ranges between 66 and 98 hours Most chemotherapy schedules for the treatment of advanced colorectal cancer are administered on an every two weeks basis The present study was designed to determine whether cetuximab could be safely administered on an every 2-week schedule

3. Aims of the study Primary objective To determine the MTD/RD of cetuximab when administered to patients with EGFR-expressing mCRC on an every 2 weeks schedule (q2w) for 6 weeks based on DLTs Secondary objectives To assess PK parameters of cetuximab given at the approved dose and schedule (q1w) and at different dose levels on an q2w schedule To determine PD effects of cetuximab, given q1w and at different dose levels on an q2w schedule, measured in skin, tumor and serum samples To evaluate overall response rate and progression-free survival time To evaluate the safety of cetuximab as single agent and in combination with an irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) [FOLFIRI]) regimen

4. Study design (I) Phase I, open-label, multicenter study Planned recruitment was 20-50 patients, depending on observed DLTs DLTs were defined as: –Any grade 3-4 toxicity except for infusion-related reaction or grade 3 skin reaction –Administration of 14 days in first 6 weeks) because of side effects at any of the cetuximab doses

5. Study design (II) Skin and tumor biopsies were taken at baseline and on day 28 Blood samples for PK analysis –Group A (q1w standard regimen): week 1: pre-dose and end of infusion (EOI) week 2, 3 and 4: pre-dose week 5: 0, EOI, 4, 24, 48, 96 and 168 hours –Group B (q2w escalation): week 1: pre-dose and EOI week 3: pre-dose week 5: pre-dose, EOI, 4, 24, 48, 96, 168, 240, 288 and 336 hours –Starting on week 7, blood samples were collected prior to each cetuximab infusion (trough concentrations) until PD PK parameters were calculated according to non-compartmental standard methods

6. Study design (III) *Simplified FOLFIRI: irinotecan 180 mg/m 2 over 30-90 min, FA 400 mg/m 2 120 min, 5-fluorouracil (5-FU) 400 mg/m 2 as bolus and 2400 mg/m 2 as infusion over 46 hours, given every 2 weeks; PFS: progression-free survival

7. Patients. Eligibility criteria Main inclusion criteria: ≥18 years of age Histologically confirmed EGFR-expressing mCRC with ≥1 tumor accessible for repeated biopsy and with measurable disease ≥1 bi-dimensionally measurable lesion, not in an irradiated area ECOG PS ≤2, adequate bone marrow, renal and hepatic parameters Main exclusion criteria: Previous exposure to EGFR-targeting therapy; previous chemotherapy for mCRC or adjuvant therapy within the last 6 months before study entry Clinically relevant medical diseases

8. Patient baseline characteristics

9. Results: Pharmacokinetics I Twenty nine patients have been assessed to date PKs are comparable between q1w and 500 mg/m² q2w regimens The increases in Cmin and AUC between 400 and 500 mg/m² q2w regimens are dose proportional Trough concentration values of the 500 mg/m² q2w regimen are comparable to the current standard q1w regimen (400/250 mg/m²)

10. Results: Pharmacokinetics II Peak concentrations were determined in weeks 1 and 5 only; trough concentrations were determined in weeks 1, 2, 3, 4, 5, 6 and 7 for the standard regimen and in weeks 1, 3, 5 and 7 for the experimental regimens

11. Results: Pharmacodynamics in skin pEGFR pMAPK Proliferation (Ki67)p27 Preliminary skin PD studies, based on a limited number of samples, show no major differences in the inhibition of EGFR-signaling by cetuximab between the q1w and the q2w regimens

12. Safety Safety results in the first 6 weeks (cetuximab single agent) of treatment on an ITT basis in the 2 different schedules Neither DLTs nor grade 4 adverse events have been observed to date *One patient in group A experienced a SAE during Part 1 of the study: intraparenchymatous liver hematoma related to biopsy * *

13. Conclusions I Cetuximab can be safely administered q2w at 400-500 mg/m 2 Cetuximab at 500 mg/m 2 q2w rather than 400 mg/m 2 q2w has similar PKs compared to the current standard q1w regimen at steady state (week 5) –AUC at 500 mg/m 2 q2w (34953 µg/mL*h) is ≈ to AUC achieved with 2 weeks of standard cetuximab dosing q1w (2 x 17278 µg/mL*h), suggesting similar exposure as for the standard weekly regimen –Minimum cetuximab concentration after 500 mg/m 2 q2w is close to the minimum concentration with the current standard q1w regimen The MTD of cetuximab given q2w has not yet been reached Preliminary skin PD studies, based on a limited number of samples, show no major difference in the EGFR-signaling inhibition by cetuximab in the q1w and q2w regimens Cetuximab given every two weeks may be an alternative and convenient schedule of administration

14. Contributors Vall d’Hebron University Hospital Medical Oncology Department –Francisco J. Ramos –Teresa Macarulla –Esther Casado –Marta Parera –Josep Tabernero –José Baselga Pathology Department –Fredy Rojo –José Jiménez –Santiago Ramon y Cajal Hospital Clínico de Valencia –A. Pérez-Fidalgo –Andrés Cervantes Second University of Naples –Erika Martinelli –Fortunato Giardiello Hospital Marques de Valdecilla –Eugenia Vega-Villegas –Fernando Rivera Merck KGaA –Antoni Mesa –Oliver Kisker –Angela Zuber –Andreas Harstrich