FDA approves Votrient® for treatment of patients with certain types of advanced soft tissue sarcoma

Issued: Philadelphia

GlaxoSmithKline plc [LSE/NYSE: GSK] announced today that the U.S. Food and Drug Administration (FDA) has approved Votrient^® (pazopanib) for the treatment of patients with advanced soft tissue sarcoma who have received prior chemotherapy. The U.S. label contains the following limitations: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

“It is such a great moment to bring forth this treatment option for patients, as it represents one of the few new medical options to be provided to patients with advanced soft tissue sarcoma over the last thirty years,” said Paolo Paoletti, M.D., President, GSK Oncology. “GSK Oncology feels fortunate to have collaborated with the European Organization for Research and Treatment of Cancer (EORTC) in completing a rigorous Phase III trial in such a rare cancer.”

The approval for VOTRIENT is based on the results of the pivotal, randomized, double-blind, placebo controlled, multi-centre Phase III study called PALETTE (PAzopanib ExpLorEd in sofT Tissue sarcoma).  More information on this trial can be found in the full U.S. Prescribing Information found at http://www.gsksource.com/gskprm/htdocs/documents/VOTRIENT-PI-MG.PDF.

About Soft Tissue Sarcoma (STS)

Soft tissue sarcomas constitute a group of rare cancers arising from mesenchymal cells. These cells normally give rise to soft tissues including fat, muscle, nerve, blood vessels and other connective tissues. The incidence of STS in 2011 in the U.S. was 10,980 patients, according to the American Cancer Society. Fewer patients have advanced STS for which they previously received chemotherapy. The composition of the PALETTE trial population was further limited because patients with GIST or adipocytic sarcomas were not included. 

About pazopanib (VOTRIENT)

Votrient^® (pazopanib) 200 mg tablets is now approved for the treatment of patients with advanced soft tissue sarcoma who have received prior chemotherapy. Limitation of Use:  The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.  VOTRIENT, an oral medication, was approved for the treatment of advanced renal cell carcinoma in adults in 2009 in the United States.  

For more information about VOTRIENT, including full U.S. Prescribing Information, BOXED WARNING and Medication Guide, please visit  http://www.gsksource.com/gskprm/htdocs/documents/VOTRIENT-PI-MG.PDF.

Important Safety Information for VOTRIENT

WARNING: HEPATOTOXICITY
Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment,monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.  

Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 

Hemorrhagic Events:  Hemorrhagic events have occurred and can be fatal. VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months.  

Arterial Thrombotic Events: Arterial thrombotic events have occurred and can be fatal.  Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months.

Venous Thromboembolic Events:  Venous thromboembolic events have occurred, including fatal pulmonary emboli; monitor for signs and symptoms.

Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred, including fatal perforation events. Use with caution in patients at risk for these events and monitor for signs and symptoms.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Discontinue VOTRIENT in patients developing RPLS.  

Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than one week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT.

Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence.  

Hypothyroidism: Hypothyroidism has occurred. Monitoring of thyroid function tests is recommended.  

Proteinuria: Proteinuria has occurred. Monitor urine protein. Interrupt treatment for 24-hour urine protein =3 grams and discontinue for repeat episodes despite dose reductions.  

Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider discontinuation of VOTRIENT.  

Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed.  

Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.  

Pneumothorax:  Pneumothorax has occurred (8/240 STS patients (3%) treated with VOTRIENT vs. 0% in the placebo group).  

Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of VOTRIENT and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit juice.  

Concomitant use of strong CYP3A4 inducers (e.g., rifampin) should be avoided due to potential to decrease concentrations of VOTRIENT.  VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.  

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.  

Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring.  

Adverse Reactions: The most common adverse reactions (=20%) in subjects with STS who received VOTRIENT versus placebo were fatigue (65% vs. 48%), diarrhea (59% vs. 15%), nausea (56% vs. 22%), decreased weight (48% vs. 15%), hypertension (42% vs. 6%), decreased appetite (40% vs. 19%), hair color changes (39% vs. 2%), vomiting (33% vs. 11%), tumor pain (29% vs. 21%), dysgeusia (28% vs. 3%), headache (23% vs. 8%), musculoskeletal pain (23% vs. 20%), myalgia (23% vs. 9%), gastrointestinal pain (23% vs. 9%), dyspnea (20% vs 17%).

Laboratory abnormalities occurring in >10% of STS subjects and more commonly (=5%) in the VOTRIENT arm versus placebo included increases in AST (51% vs. 22%), ALT (46% vs. 18%), glucose (45% vs. 35%), alkaline phosphatase (32% vs. 23%), total bilirubin (29% vs. 7%), and potassium (16% vs. 11%); decreases in sodium (31% vs. 20%) and albumin (34% vs. 21%); and leukopenia (44% vs. 15%), lymphocytopenia (43% vs. 36%), thrombocytopenia (36% vs. 6%), and neutropenia (33% vs. 7%).

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Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK' s operations are described under 'Risk factors' in the 'Financial review & risk' section in the company's Annual Report 2011 included as exhibit 15.2 to the company's Annual Report on Form 20-F for 2011.