Rash severity and dose in phase I dose escalation cetuximab (C225) trial

Abstract

14573 Background: C225 is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The FDA-approved dose is 400 mg/m2 loading with weekly maintenance at 250 mg/m2. C225 efficacy has been correlated with grade of skin rash, which is reported to be dose dependent. This study examined the safety and feasibility of escalating weekly C225 doses, and evaluated skin rash as a surrogate for tumor response. Methods: Four dose levels were tested: C225 400 mg/m2 loading and 250, 300, 350, 400 mg/m2 weekly maintenance. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, Gr 4 cutaneous toxicity, Gr 3 cutaneous toxicity necessitating holding C225 for > 4 weeks, or other ≥ Gr 3 non-hematologic toxicity. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (Int J Derml 36:416–18, 1997; J Am Acad Derm 35:559–65, 1996). Tumor specimens and blood samples were obtained for correlative analyses. Results: Twenty-six patients (pts) with advanced solid tumors were treated, including: 5 head & neck, 3 pancreas, 3 cholangiocarcinoma, 2 each of prostate, breast, colorectal, lung, and esophagus, and 5 others. Characteristics: Age range 44–84, median 60; Gender: 19 M; KPS ≥80 = 15; Prior chemo ≤1= 6; Median cycles 2 (1–8). Planned dose escalation was completed without DLTs nor reaching the MTD. The highest dose level was expanded to 17 pts total. Gr 3/4 toxicities were: lymphopenia (2), fatigue (2), acneiform rash (1), hypomagnesemia (1), and elevated GGT (1). In 22 evaluable pts, there was 1 partial response (PR) in a pt with cholangiocarinoma, and 7 with stable disease (SD). 65% of pts had a ≥ Gr 2 rash that was not dose dependent. GAGS and acne grading scale analyses will be described. In ongoing analyses, 1 of 9 pts had a KRAS mutation (pancreas, PD), 1 of 8 had EGFR amplification by FISH (heavily pre-treated breast, SD). Additional planned correlatives include EGFR polymorphisms and tumor/plasma levels of EGFR ligands. Conclusions: 1) C225 400 mg/m2 loading with 400 mg/m2 maintenance is feasible and well tolerated. 2) Grade of rash is not dose dependent using the CTCAE v3.0 and does not correlate with response in this limited cohort. 3) Novel methods of evaluating rash are required. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OSI Oncology Bristol-Myers Squibb Bristol-Myers Squibb