Dataset Information

Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study.

ABSTRACT: To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies.Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m(2) to patients who were not (stratum I) or were (stratum II) receiving steroids. Pharmacokinetic studies were performed during the first two courses. Expression of the four ERBB receptors and downstream signaling elements in tumor tissue was evaluated by immunohistochemistry.Fifty-nine patients were enrolled (stratum I, n = 32; stratum II, n = 27). Of 29 patients evaluable for toxicity in stratum I, one experienced a DLT (diarrhea) at 520 mg/m(2) twice daily, and all three receiving 1,150 mg/m(2) twice daily experienced DLTs (one each of rash, diarrhea, and fatigue). Two of 21 patients evaluable for toxicity in stratum II experienced DLTs of rash at 900 mg/m(2) twice daily. Lapatinib dosage was related linearly to area under the [concentration-time] curve from start time to 12 hours later (AUC(0-12)) and dose-normalized maximum serum concentration and AUC values for patients in stratum II were both significantly higher (P = .001) than those for patients in stratum I. Frequent, high-level expression of activated (phosphorylated) EGFR and ERBB2 receptors and downstream signal intermediates were observed in tumors, particularly in ependymomas that displayed prolonged stable disease on lapatinib therapy.Lapatinib is well tolerated in children with recurrent CNS malignancies, with rash, diarrhea, and fatigue identified as DLTs. The recommended phase II dose, regardless of steroid use, is 900 mg/m(2) twice daily.

SUBMITTER: Fouladi M

PROVIDER: S-EPMC2953974 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study.

Fouladi Maryam M Stewart Clinton F CF Blaney Susan M SM Onar-Thomas Arzu A Schaiquevich Paula P Packer Roger J RJ Gajjar Amar A Kun Larry E LE Boyett James M JM Gilbertson Richard J RJ

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100816 27

<h4>Purpose</h4>To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies.<h4>Patients and methods</h4>Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m(2) to patients who were not (stratum I) or were (stratum II) receiving steroids. Pharmacokinetic studies were performed ...[more]

PMID: 20713864

Similar Datasets

Project description:BackgroundAcquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors.MethodsPatients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies.ResultsTwenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders.ConclusionsThe combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.

Dataset Information

Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study.

Publications

Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets