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

Background

• Cetuximab mean t1/2 values increase as the dose of cetuximab

increases from 20 mg/m2 to 200 mg/m2

• At the recommended dosing regimen of a 400 mg/m2 initial dose

followed by 250 mg/m2 weekly, mean t1/2 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

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

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 <66% of assigned dose (i.e. delay of >14 days in first 6 weeks) because of side effects at any of the cetuximab doses

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

Study design (III)

*Simplified FOLFIRI: irinotecan 180 mg/m2 over 30-90 min, FA 400 mg/m2 120 min, 5-fluorouracil (5-FU)400 mg/m2 as bolus and 2400 mg/m2 as infusion over 46 hours, given every 2 weeks; PFS: progression-freesurvival

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

Patient baseline characteristics

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)

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

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

SafetySafety 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

**

Conclusions I

• Cetuximab can be safely administered q2w at 400-500 mg/m2

• Cetuximab at 500 mg/m2 q2w rather than 400 mg/m2 q2w has similar PKs compared to the current standard q1w regimen at steady state (week 5)

– AUC at 500 mg/m2 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/m2 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

ContributorsVall 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