Optimal dose of cetuximab (C) 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)

Abstract

3085 Background: The anti-EGFR Mab C is active in mCRC. Since C has a long terminal half-life and it is frequently given in combination with q2w chemotherapy, we decided to compare the safety and PK/PD of a more convenient q2w schedule with the currently approved q1w schedule in pts with EGFR-expressing mCRC. Methods: In this study C was given q2w at the standard q1w regimen (400 mg/m2 initial dose and 250 mg/m2 weekly) to 10 pts as a comparator. In the experimental arm, C was given q2w with a dose escalation in sequential steps for cohorts of 10 pts each (400, 500, 600 & 700 mg/m2). Dose levels were escalated if no dose-limiting toxicities (DLTs) were observed. DLTs were defined as grade 3–4 toxicities (except for hypersensitivity reactions and grade 3 skin toxicity), and/or administration of less than 66% of the assigned dose due to toxicity. In order to conduct the PK/PD studies, all treatment groups were given C alone for 6 weeks and subsequently, the FOLFIRI regimen was added. Complete PK profile was obtained during the initial 6 weeks of treatment. Skin and tumor biopsies for PD profiling were obtained prior to therapy and on day 28 (steady state) and have been analyzed by IHC for total (t) and phospho (p)-EGFR, p-MAPK, p-Akt, proliferation (Ki67) & p27 expression. Results: 29 pts have been included so far: 9 in the q1w group and 20 in the q2w group (10 pts each at 400 and 500 mg/m2). To date there have been no DLTs. PK data are predictable (Cmin, AUC) and comparable (t1/2, CLss) between both regimens (see table below). Preliminary skin PD studies show no major difference in the EGFR-signaling inhibition by C in the q1w and q2w regimens. Conclusions: C can be safely administered in a q2w regimen at 400 and 500 mg/m2. The MTD of q2w C has not yet been reached and dose escalation is ongoing. Our findings show no major difference in PK and PD profiles with the q1w and q2w schedules. C given q2w may be an alternative and convenient schedule of administration. [Table: see text] [Table: see text]