A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors

A Children’s Oncology Group phase 1 and pilot consortium trial (ADVL1315)

James I. Geller, Elizabeth Fox, Brian K. Turpin, Stuart L. Goldstein, Xiaowei Liu, Charles G. Minard, Rachel A. Kudgus, Joel M. Reid, Stacey L. Berg, Brenda J Weigel

Research output: Contribution to journalArticle

Abstract

Background: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors. Methods: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m2/dose and 3.2 mg/m2/dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed. Results: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≥6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified. Conclusions: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m2/dose, which provides PK exposures similar to those of adults.

Original languageEnglish (US)
Pages (from-to)4548-4555
Number of pages8
JournalCancer
Volume124
Issue number23
DOIs
StatePublished - Dec 1 2018

Fingerprint

Vascular Endothelial Growth Factor Receptor
Protein-Tyrosine Kinases
Neoplasms
Pharmacokinetics
Hypertension
axitinib
Alveolar Soft Part Sarcoma
Biomarkers
Vascular Endothelial Growth Factor Receptor-1
Ewing's Sarcoma
Maximum Tolerated Dose
Neurilemmoma
Receptor Protein-Tyrosine Kinases
Anorexia
Osteosarcoma
Lipase
Nausea
Fatigue
Half-Life
Anemia

Keywords

  • Inlyta
  • axitinib
  • pediatric solid tumor
  • phase 1
  • vascular endothelial growth factor receptor (VEGFR)

Cite this

A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors : A Children’s Oncology Group phase 1 and pilot consortium trial (ADVL1315). / Geller, James I.; Fox, Elizabeth; Turpin, Brian K.; Goldstein, Stuart L.; Liu, Xiaowei; Minard, Charles G.; Kudgus, Rachel A.; Reid, Joel M.; Berg, Stacey L.; Weigel, Brenda J.

In: Cancer, Vol. 124, No. 23, 01.12.2018, p. 4548-4555.

Research output: Contribution to journalArticle

Geller, James I. ; Fox, Elizabeth ; Turpin, Brian K. ; Goldstein, Stuart L. ; Liu, Xiaowei ; Minard, Charles G. ; Kudgus, Rachel A. ; Reid, Joel M. ; Berg, Stacey L. ; Weigel, Brenda J. / A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors : A Children’s Oncology Group phase 1 and pilot consortium trial (ADVL1315). In: Cancer. 2018 ; Vol. 124, No. 23. pp. 4548-4555.
@article{2aa7b3958c6d4388bcf16239bbe14263,
title = "A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors: A Children’s Oncology Group phase 1 and pilot consortium trial (ADVL1315)",
abstract = "Background: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors. Methods: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m2/dose and 3.2 mg/m2/dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed. Results: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20{\%}) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≥6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified. Conclusions: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m2/dose, which provides PK exposures similar to those of adults.",
keywords = "Inlyta, axitinib, pediatric solid tumor, phase 1, vascular endothelial growth factor receptor (VEGFR)",
author = "Geller, {James I.} and Elizabeth Fox and Turpin, {Brian K.} and Goldstein, {Stuart L.} and Xiaowei Liu and Minard, {Charles G.} and Kudgus, {Rachel A.} and Reid, {Joel M.} and Berg, {Stacey L.} and Weigel, {Brenda J}",
year = "2018",
month = "12",
day = "1",
doi = "10.1002/cncr.31725",
language = "English (US)",
volume = "124",
pages = "4548--4555",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "23",

}

TY - JOUR

T1 - A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors

T2 - A Children’s Oncology Group phase 1 and pilot consortium trial (ADVL1315)

AU - Geller, James I.

AU - Fox, Elizabeth

AU - Turpin, Brian K.

AU - Goldstein, Stuart L.

AU - Liu, Xiaowei

AU - Minard, Charles G.

AU - Kudgus, Rachel A.

AU - Reid, Joel M.

AU - Berg, Stacey L.

AU - Weigel, Brenda J

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Background: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors. Methods: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m2/dose and 3.2 mg/m2/dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed. Results: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≥6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified. Conclusions: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m2/dose, which provides PK exposures similar to those of adults.

AB - Background: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors. Methods: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m2/dose and 3.2 mg/m2/dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed. Results: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≥6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified. Conclusions: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m2/dose, which provides PK exposures similar to those of adults.

KW - Inlyta

KW - axitinib

KW - pediatric solid tumor

KW - phase 1

KW - vascular endothelial growth factor receptor (VEGFR)

UR - http://www.scopus.com/inward/record.url?scp=85056097679&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056097679&partnerID=8YFLogxK

U2 - 10.1002/cncr.31725

DO - 10.1002/cncr.31725

M3 - Article

VL - 124

SP - 4548

EP - 4555

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 23

ER -