Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04–02)

Abstract

2057 Background: Glioblastomas (GBM) frequently have amplification/mutation of EGFR and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have only modest activity, there is a rationale for combinations of these agents. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor CCI-779 in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, > 18 yrs old, KPS > 60, adequate bone marrow reserve and organ function. Patients (pts) must not be receiving enzyme inducing antiepileptic drugs. The dose of erlotinib was fixed at 150 mg/d. Patients initially received CCI-779 50 mg intravenously once weekly and the dose was adjusted based on toxicities. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade (G) 4 hematologic toxicity except for G3 thrombocytopenia, and any G3 or unacceptable G2 non-hematologic toxicities. Escalation was performed in groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 pts. Results: To date 22 eligible pts have been enrolled (15 GBM; 7 AG). Patient characteristics were 12 male, 10 female; median age: 54 (26–74); median KPS 90 (70–100); median prior chemotherapy regimens 1 (0–3). Two of 3 pts receiving 50 mg of CCI-779 developed DLTs (intolerable G2 rash & mucositis, & G3 liver function abnormalities; G3 rash & dehydration). Three of 6 pts receiving 25 mg of CCI-779 weekly experienced DLTs (G3 rash; G3 rash, diarrhea, dehydration; G3 mucositis & infection). Two of 6 patients receiving weekly 15 mg of CCI-779 experienced G3 rash. The protocol was amended to define a DLT only if > G3 toxicities persisted despite maximal therapy. Six additional pts were treated at 15 mg of CCI-779. One of 6 pts developed a G3 rash. Conclusions: The combination of erlotinib and CCI-779 was associated with a higher than expected incidence of rash and mucositis. The MTD for this combination is likely to be 150 mg/d of erlotinib and 15 mg/d of CCI-779. Final pharmacokinetics and response data will be presented. No significant financial relationships to disclose.