FDA Approval for Pazopanib Hydrochloride
Brand name(s): Votrient®
Full prescribing information is available, including boxed warning for severe and fatal hepatotoxicity, clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
On April 26, 2012, the FDA approved pazopanib hydrochloride tablets (Votrient®, made by GlaxoSmithKline) for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. The efficacy of pazopanib hydrochloride for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.
The trial enrolled 369 patients who were randomly allocated (2:1) to receive pazopanib hydrochloride 800 mg orally once daily (N=246) or placebo (N=123). Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The majority of patients were female (59 percent), and the median age was 55. Forty-three percent of patients had leiomyosarcoma, 10 percent had synovial sarcoma, and 47 percent had other soft tissue sarcomas. Fifty-six percent had received two or more prior systemic therapies. The median treatment duration was 4.5 months for patients receiving pazopanib hydrochloride and 1.9 months for patients receiving placebo.
A statistically significant improvement in progression-free survival (PFS) in patients receiving pazopanib hydrochloride compared with those receiving placebo was demonstrated (HR = 0.35; 95 percent CI: 0.26, 0.48; p< 0.001, log-rank test)]. The median PFS was 4.6 months for patients receiving pazopanib hydrochloride and 1.6 months for patients receiving placebo. The PFS improvements in the three pre-specified histological subgroups of leiomyosarcoma (HR = 0.37; 95 percent CI: 0.23, 0.60), synovial sarcoma (HR = 0.43; 95 percent CI: 0.19, 0.98) and other soft tissue sarcomas (HR = 0.39; 95 percent CI: 0.25, 0.60) were consistent with the PFS improvement in the overall population.
The objective response rate was 4 percent for patients receiving pazopanib hydrochloride; no patient receiving placebo was noted to have a response. At the protocol-specified final analysis of overall survival, the median survival was 12.6 months for patients receiving pazopanib hydrochloride and 10.7 months for patients receiving placebo (HR = 0.87; 95 percent CI: 0.67, 1.12).
The most common adverse reactions in STS patients treated with pazopanib hydrochloride ( at least 20 percent of patients) were fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation. Other significant adverse reactions included hepatic toxicity, arterial and venous thrombotic events, hemorrhage, gastrointestinal perforation and fistula formation, pneumothorax, and left ventricular dysfunction.
The recommended dose and schedule of pazopanib hydrochloride is 800 mg orally once daily, administered without food (at least 1 hour before or 2 hours after a meal).
On October 19, 2009, the FDA granted approval to pazopanib hydrochloride tablets (Votrient®, made by GlaxoSmithKline) for the treatment of patients with advanced renal cell carcinoma.
The efficacy and safety of pazopanib hydrochloride were evaluated in an international, multicenter, randomized, double-blind trial comparing pazopanib to placebo. All patients received best supportive care. The trial was conducted in patients with metastatic renal cell carcinoma who had not received prior treatment or who had received prior cytokine therapy. Randomization was stratified according to performance status, prior nephrectomy, and prior cytokine therapy.
A total of 435 patients were randomly assigned (2:1) to receive pazopanib hydrochloride (n=290) or placebo (n=145). Demographics were balanced between the two arms of the trial. Progression-free survival (PFS) was the trial's primary endpoint. The median PFS was 9.2 months in the pazopanib hydrochloride arm and 4.2 months in the placebo arm, (HR = 0.46, p value < 0.001). The effect was observed in both patients who had not received prior treatment (HR = 0.40) and patients pre-treated with cytokine therapy (HR = 0.54). After documented radiological progression, patients receiving placebo could receive pazopanib.
The overall survival results are not mature; 40 percent of patients had died by the time of data cut-off. The objective response rates were 30 percent for those treated with pazopanib hydrochloride and 3 percent for those treated with placebo. The median duration of responses was 13.5 months.
The most common adverse reactions, reported in 20 percent of patients, were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. Grade 3/4 adverse reactions that differed at least two percent between arms were abnormal hepatic function, diarrhea, hypertension, and proteinuria (excess of blood serum proteins in urine). QT prolongation (a measure of heart function) has been seen with pazopanib. Laboratory abnormalities occurring in at least ten percent of all patients and more commonly reported in the pazopanib hydrochloride arm included increased transaminases (liver enzymes), hyperglycemia, leukopenia, hyperbilirubinemia, neutropenia, hypophosphatemia, thrombocytopenia, lymphocytopenia, hyponatremia (low level of sodium in the blood), hypomagnesemia (low level of magnesium in the blood), and hypoglycemia. Deaths due to serious adverse events including cerebrovascular accident (stroke), gastric cancer, gastrointestinal hemorrhage, hemoptysis, bowel perforation, cardiac failure, myocardial infarction (heart attack), hepatic failure and pneumonia occurred more commonly in the pazopanib arm. Hepatic dysfunction is included as a boxed warning in the product label and two deaths were associated with hepatic failure.
Liver tests should be monitored every four weeks for at least the first four months with periodic monitoring thereafter. Recommended dose modifications for pazopanib hydrochloride in patients with abnormal liver tests are included in the package insert. EKG and electrolytes should be monitored.
The recommended dose of pazopanib hydrochloride for treatment of advanced renal cell carcinoma is 800 mg, once daily at the same time without food (at least one hour before or two hours after a meal).
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.