Pediatric phase I trial and pharmacokinetic study of trebananib in relapsed solid tumors, including primary tumors of the central nervous system ADVL1115: A children's oncology group phase I consortium report

Sarah E.S. Leary, Julie R. Park, Joel M. Reid, Andrew T. Ralya, Sylvain Baruchel, Bing Wu, Timothy P.L. Roberts, Xiaowei Liu, Charles G. Minard, Elizabeth Fox, Brenda Weigel, Susan Blaney

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood bio-markers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI. Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI. Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg.

Original languageEnglish (US)
Pages (from-to)6062-6070
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2017

Bibliographical note

Funding Information:
Research was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award number UM1 CA097452, Cookies for Kids' Cancer Foundation and the Children's Oncology Group Foundation.

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