Download - Background
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