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.

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 biomarkers 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. Clin Cancer Res; 23(20); 6062-9. ©2017 AACR.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 20 Pg. 6062-6069 (Oct 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28751444 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• Recombinant Fusion Proteins
• trebananib

Topics

• Adolescent
• Age Factors
• Antineoplastic Agents, Immunological (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Central Nervous System Neoplasms (diagnostic imaging, drug therapy, pathology)
• Child
• Child, Preschool
• Female
• Humans
• Magnetic Resonance Imaging
• Male
• Neoplasms (diagnostic imaging, drug therapy, pathology)
• Recombinant Fusion Proteins (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Recurrence
• Retreatment
• Treatment Outcome
• Young Adult