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
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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). 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. 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 ( = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension ( = 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. Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. .
Spini A, Ciccone V, Rosellini P, Ziche M, Lucenteforte E, Salvo F Cancers (Basel). 2022; 14(21).
PMID: 36358734 PMC: 9654149. DOI: 10.3390/cancers14215315.
Ioannidou E, Moschetta M, Shah S, Parker J, Ozturk M, Pappas-Gogos G Int J Mol Sci. 2021; 22(18).
PMID: 34576107 PMC: 8472415. DOI: 10.3390/ijms22189926.
Use of Antiangiogenic Therapies in Pediatric Solid Tumors.
Ollauri-Ibanez C, Astigarraga I Cancers (Basel). 2021; 13(2).
PMID: 33445470 PMC: 7827326. DOI: 10.3390/cancers13020253.
Carmagnani Pestana R, Hassan M, Abdel-Wahab R, Abugabal Y, Girard L, Li D Oncotarget. 2019; 9(102):37721-37732.
PMID: 30701027 PMC: 6340869. DOI: 10.18632/oncotarget.26507.