A pediatric phase I trial and pharmacokinetic (PK) study of erlotinib (ERL) followed by the combination of ERL with temozolomide (TMZ): A Children’s Oncology Group Study

Abstract

9015 Background: EGFR is potently inhibited by ERL. Aberrant cell signaling via the EGFR family has been implicated in the development of several human cancers, including certain pediatric solid tumors. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the maximal tolerated dose (MTD) and dose limiting toxicities (DLTs) of single agent ERL, determine the tolerability of the combination of ERL and TMZ, and to determine the PK of ERL. Pts received single agent ERL qd × 28 d followed by ERL qd continuously in combination with TMZ 180 mg/m2/day × 5d. Cycles were repeated q 28 d. ERL was initially administered using the IV formulation given orally. The tablet form was subsequently studied at the MTD to further evaluate PK. Results: 46 pts (36 fully evaluable for toxicity) median age 11.5 yrs (range 3–20 yrs), were enrolled in cohorts of 3–6 pts at ERL doses of 35, 50, 65, 85 and 110 mg/m2/d. At the 110 mg/m2/day dose level, 2/4 pts had DLT (1 rash, 1 hyperbilirubinemia). In the expanded cohort at the MTD of 85 mg/m2/d, (n=21), 3 pts had DLT (2 rash, 1 diarrhea). Non-DLTs observed during the single agent cycle included diarrhea (n=14), rash (n=9), hyperbilirubinemia (n=7), neutropenia and/or thrombocytopenia (n=5). 1 pt with a soft tissue sarcoma had a minor response after 28d of single agent ERL, continuing to a PR by cycle 4. 3 pts (2 neuroblastoma, 1 neurocytoma) had prolonged responses (13–20+ months) to the combination. Oral administration of the IV formulation resulted in a higher Cmax and a lower Cmin compared to the adult data using tablets. Median apparent clearance was 2.85 (range 1.61–6.37) L/hr/m2 with a terminal half of 8.45 (5.1–27.1) hr. No PK interaction was observed between ERL and TMZ and the combination was well tolerated. Conclusions: The pediatric recommended phase 2 dose of ERL of 85 mg/m2/day, either alone or in combination with TMZ, is well tolerated in children. A COG phase 2 trial is planned. [Table: see text]