A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group

Meredith K. Chuk, Brigitte C. Widemann, Charles G. Minard, Xiaowei Liu, Ae Rang Kim, Melanie Brooke Bernhardt, Rachel A. Kudgus, Joel M Reid, Stephan D. Voss, Susan Blaney, Elizabeth Fox, Brenda J. Weigel

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Methods: Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Results: Forty-one patients, median (range) age 13 (4–18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m2/day. At 40 mg/m2/d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m2/d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). Conclusions: A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m2/day. A phase 2 study of cabozantinib is being conducted.

Original languageEnglish (US)
Article numbere27077
JournalPediatric Blood and Cancer
Volume65
Issue number8
DOIs
StatePublished - Aug 1 2018

Keywords

  • cabozantinib
  • pediatrics
  • phase 1

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Fingerprint Dive into the research topics of 'A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group'. Together they form a unique fingerprint.

  • Cite this

    Chuk, M. K., Widemann, B. C., Minard, C. G., Liu, X., Kim, A. R., Bernhardt, M. B., Kudgus, R. A., Reid, J. M., Voss, S. D., Blaney, S., Fox, E., & Weigel, B. J. (2018). A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group. Pediatric Blood and Cancer, 65(8), [e27077]. https://doi.org/10.1002/pbc.27077