Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma

Endocrine. 2017 Aug;57(2):220-225. doi: 10.1007/s12020-017-1359-5. Epub 2017 Jul 6.

Abstract

Introduction: Pheochromocytomas and paragangliomas (Pheo/PGL) are rare, vascular, sometimes malignant endocrine tumors. Case reports indicate the activity of vascular endothelium growth factor receptor-targeted kinase inhibitors in these cancers.

Objectives: To assess the antitumor activity and tolerability of pazopanib in progressive malignant Pheo/PGL.

Patients and methods: This multicenter Phase II trial (MC107C) enrolled individuals ≥18 years old with disease progression ≤ 6 months prior to registration, Eastern Cooperative Oncology Group PS 0-2, and measurable disease (response evaluation criteria in solid tumors 1.0). Pazopanib was administered in 28-day cycles, with the regimen ultimately being as follows: cycle 1: 400 mg daily on days 1-14, cycle 2: 800 mg daily on days 1-14, and then cycle 2 + : 800 mg daily on all days.

Results: The study was halted due to poor accrual. Seven patients were enrolled (05/2011-11/2014). One patient withdrew consent prior to treatment, leaving six evaluable patients. Treatment was discontinued, due to the following reasons: disease progression (4); withdrawal (1); and grade 4 (Takotsubo) cardiomyopathy (1). The median number of cycles administered was 4 (range: 2-29, total: 49). Four patients had >1 dose reduction due to the following reasons: fatigue (1), abnormal liver tests (2), hypertension and (Takotsubo) cardiomyopathy (1), and headaches (1). Common severe (Common Terminology Criteria for Adverse Events v3.0 grades 3-5) toxicities were as follows: hypertension (3/6), (Takotsubo) cardiomyopathy (2/6), diarrhea (1/6), fatigue (1/6), headache (1/6), and hematuria (1/6). One confirmed partial response was observed in PGL (17%, duration 2.4 years); median progression-free survival and overall survival were 6.5 and 14.8 months, respectively.

Conclusion: Pazopanib has activity in Pheo/PGL requiring more study; optimal alpha- and beta-blockade are imperative pre-therapy in patients with secretory tumors, as risk of hypertension and cardiomyopathy are potentially life threatening.

Keywords: Metastatic; Paraganglioma; Pazopanib; Takotsubo cardiomyopathy.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adrenal Gland Neoplasms / drug therapy*
  • Adrenal Gland Neoplasms / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use*
  • Disease-Free Survival
  • Electrocardiography
  • Endocrine Gland Neoplasms / drug therapy*
  • Endocrine Gland Neoplasms / pathology
  • Female
  • Humans
  • Indazoles
  • Male
  • Middle Aged
  • Paraganglioma / drug therapy*
  • Paraganglioma / pathology
  • Pheochromocytoma / drug therapy*
  • Pheochromocytoma / pathology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use*
  • Treatment Failure

Substances

  • Angiogenesis Inhibitors
  • Indazoles
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Sulfonamides
  • pazopanib
  • Receptors, Vascular Endothelial Growth Factor