Pazopanib (Votrient)

A tyrosine kinase inhibitor indicated for the treatment of advanced renal cancer.

Approved for treatment of soft-tissue sarcoma who have previously received chemotherapy.

Alveolar soft part sarcoma responds to anti-angiogenic agents like pazopanib, with response rates 35-60%.

The drug targets VEGF-1,2,3, PDGF, and c-kit.

Inhibits fibroblast growth factor receptors 1 and 3.

An Interleukin-2 receptor inducible T-cell kinase inhibitor.

Inhibits leukocyte-specific protein kinase

Inhibits transmembrae glycoprotein receptor kinase

An oral angiogenesis inhibitor.

A potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis

Trade name Votrient.

Demonstrates an overall median progression free survival in metastatic renal cell cancer of 9.2 months versus 4.2 months with placebo.

In soft tissue sarcomas may produce long-term responses in a minority of patients.

In a phase II study 36% of patients were long-term responders, defined as having progression free survival for at least 6 months after starting therapy, and 34% of patients were alive at 18 months.

May the associated with hepatic toxicity and impairment.

May prolong the QT interval and associated with torsades de pointes.

Recommended dosage 800 mg daily without food at least one hour before or 2 hours after a meal.

Tablets are 200 mg.

May be associated with severe and fatal hepatotoxicity.

With hepatic impairment dose reduction to 200 mg daily.

May be associated with prolonged QT intervals and torsades de pointes.

Because hemorrhage can occur in patients with hemoptysis, cerebral hemorrhage or gastrointestinal bleeding in the past six months, this agent should not be used in those patients.

May be associated with arterial thrombosis.

May be associated with gastrointestinal perforation.

Blood pressure should be monitored as hypertension, may occur.

Associated with diarrhea 52%, hypertension 40%, and hair color change 38%.

Transaminase increase is most frequently associated lab abnormality.

Thyroid monitoring is recommended as the drug may be associated with hypothyroidism.

Cardiac dysfunction, CHF, and decreased left ventricular ejection fraction has occurred.

Transaminase elevation is most frequent treatment related lab abnormality.

Potential risk for hepatotoxicity.

Urine protein should be monitored for proteinuria and the drug should be discontinued for grade 4 proteinuria.

In a study of 435 patient’s with locally advanced and/or metastatic renal cancer overall median progression free survival was 9.2 months with pazopanib versus 4.2 months with placebo, and 54% reduction in the risk of tumor progression or death (Sternberg CN).

Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred.

In the above study objective response rate was 30% compared to 3% in the placebo group, and the median duration of response was longer than 1 year (Sternberg CN).

Overall response rate is 30%, with a median duration of response greater than 1 year in patients with locally advanced or metastatic renal cancer (Sternberg CN).

In a phase 3 trial compared to placebo. As a second line or later treatment in metastatic soft tissue sarcoma. There was a significant improvement in progression free survival of 20 vs. seven weeks compared to placebo, without a significant improvement in overall survival (PALLETTE-Pazopanib Explored in Soft Tissue Sarcoma).

Most common adverse reactions are diarrhea (20%), hypertension, depigmentation of hair color, nausea, anorexia and vomiting.

Shows significant activity in GIST in patients resistant to imatinib and sunitinib (PAZOGIST Study).

Pazopanib significantly improved progression-free survival (PFS) in patients with progressive carcinoid tumors who were enrolled in a prospective randomized phase 3 trial.

Median PFS was 11.6 months for patients receiving the small molecule VEGF inhibitor, versus 8.5 months for those receiving placebo.

Toxicity risks, including an excess of hypertension.

Despite the improved PFS in the pazopanib arm, there was no improvement in overall survival.

Has been shown to prolong progression free survival after initial chemotherapy for ovarian cancer.

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