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 journalArticle

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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

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Central Nervous System Neoplasms
Pharmacokinetics
Pediatrics
Neoplasms
Angiogenic Proteins
Angiopoietin-2
Angiopoietin-1
Lymphopenia
Transient Ischemic Attack
Brain Edema
Astrocytoma
Pleural Effusion
Hydrocephalus
Neutropenia
Neuroblastoma
Platelet Count
Venous Thrombosis
Nervous System
Vomiting
Headache

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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

In: Clinical Cancer Research, Vol. 23, No. 20, 15.10.2017, p. 6062-6070.

Research output: Contribution to journalArticle

Leary, Sarah E.S. ; Park, Julie R. ; Reid, Joel M ; Ralya, Andrew T. ; Baruchel, Sylvain ; Wu, Bing ; Roberts, Timothy P.L. ; Liu, Xiaowei ; Minard, Charles G. ; Fox, Elizabeth ; Weigel, Brenda ; Blaney, Susan. / 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. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 20. pp. 6062-6070.
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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.",
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T1 - Pediatric phase I trial and pharmacokinetic study of trebananib in relapsed solid tumors, including primary tumors of the central nervous system ADVL1115

T2 - A children's oncology group phase I consortium report

AU - Leary, Sarah E.S.

AU - Park, Julie R.

AU - Reid, Joel M

AU - Ralya, Andrew T.

AU - Baruchel, Sylvain

AU - Wu, Bing

AU - Roberts, Timothy P.L.

AU - Liu, Xiaowei

AU - Minard, Charles G.

AU - Fox, Elizabeth

AU - Weigel, Brenda

AU - Blaney, Susan

PY - 2017/10/15

Y1 - 2017/10/15

N2 - 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.

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