GSK announces late-stage clinical data for VOTRIENT® (pazopanib) following chemotherapy in women with advanced epithelial ovarian cancer

Issued: London UK

Treatment with VOTRIENT following chemotherapy reduced risk of disease progression

GlaxoSmithKline (GSK) plc today announced that its Phase III clinical trial of VOTRIENT (pazopanib) as maintenance therapy in women with advanced epithelial ovarian cancer following front-line chemotherapy met the primary objective of a statistically significant improvement in the time to disease progression or death  (progression-free survival, PFS) compared to placebo. Pazopanib treatment reduced the risk of disease progression or death by 23% (HR = 0.77; 95% CI: 0.64-0.91; p = 0.0021). The median PFS for women in the pazopanib group was 17.9 months compared to 12.3 months for those in the placebo group. The incidence of serious adverse events was higher in the pazopanib group compared to the placebo group (26% vs 11%). Results were presented today at the Annual Meeting of the American Society of Clinical Oncology.

 “Ovarian cancer is a leading cause of cancer deaths among women, so we were excited to collaborate with AGO and other cooperative groups in the search for new treatments.” said Dr. Rafael Amado, Head of Oncology R&D at GSK. “This study showed that treatment with Votrient following surgery and chemotherapy extended the time that these women lived without their disease progressing. We are planning to submit regulatory applications in 2013”

At the time of data cut off, there were insufficient events to estimate median overall survival and the interim analysis showed no difference in survival between the groups.  The most common (>20%) adverse events in the pazopanib arm of this study were hypertension (54%), diarrhoea (53%), nausea (37%), headache (29%), fatigue (28%), and neutropenia (22%). The most common (=2%) serious adverse events (SAEs) in the pazopanib arm were increased ALT (4%), pyrexia (2%), increased AST (2%) and hypertension (2%).  There were three fatal SAEs in the pazopanib group and one in the placebo group.

VOTRIENT is not approved for the treatment of ovarian cancer anywhere in the world.

About the pazopanib ovarian cancer study (NCT00866697)
This was a randomised, double-blind, Phase III, placebo-controlled study to evaluate the efficacy and safety of pazopanib monotherapy as compared with placebo in women with epithelial ovarian, fallopian tube, or primary peritoneal cancer whose disease had not progressed after completing standard debulking surgery and first-line chemotherapy.  The study was sponsored by GSK and conducted by several academic research organisations (cooperative groups) led by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) under the umbrella of the Gynecologic Cancer Intergroup.

After completion of = 5 cycles of platinum-taxane chemotherapy, 940 patients were randomised 1:1 to receive 800 mg pazopanib once daily or placebo for up to 24 months (median time from diagnosis to randomisation was approximately 7 months).  Full study results will be available on the GSK Clinical Trial Register: Result Summary for 110655.

About the treatment of ovarian cancer
Standard of care for patients with ovarian cancer is surgery to reduce the size of the tumour along with chemotherapy, usually a platinum-taxane regimen[i].  Although the majority of patients with advanced epithelial ovarian cancer achieve a complete remission with first-line surgery and chemotherapy, relapse is common and recurrent disease is rarely cured[ii]^,[iii].

About VOTRIENT^® (pazopanib)

VOTRIENT (pazopanib) was first approved by the US Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma (aRCC) in October 2009. Pazopanib received conditional marketing authorisation in the EU in June 2010 for the treatment of patients with aRCC. The CHMP recommended the conversion of the conditional marketing authorisation to a full marketing authorisation in March 2013.  Pazopanib is now approved in more than 80 countries as a treatment for patients with aRCC. The therapeutic indication for pazopanib has been expanded to include treatment of patients with advanced Soft Tissue Sarcoma (aSTS), gaining US approval in April 2012 and EU approval in August 2012. Pazopanib is currently approved in more than 50 countries as a treatment for aSTS.  For full US Prescribing Information including BOXED WARNING for hepatoxocity please visit Our medicines and products - GlaxoSmithKline.  For the EU SPC for the approved indications for pazopanib, please visit GSK Health 

Important Safety Information
Hepatic Toxicity and Hepatic Impairment: The US prescribing information for VOTRIENT includes a BOXED WARNING for hepatotoxicity.  Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. 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.

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.

Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred.  Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure.

Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the RCC and STS clinical trials, the most common hemorrhagic events were hematuria, epistaxis, hemoptysis, mouth hemorrhage, and rectal/anal hemorrhage. 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.  VOTRIENT should be used with caution in patients who are at increased risk for these events and should not be used in patients who have had an arterial thrombotic event in the past 6 months.

Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. Patients should be monitored for signs and symptoms.

Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistulae have occurred and some perforation events resulted in fatality. VOTRIENT should be used 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. Permanently discontinue VOTRIENT in patients developing RPLS.

Hypertension: Hypertension, including hypertensive crisis, has occurred. 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, dose reduction, interruption or discontinuation of VOTRIENT as clinically warranted.

Wound Healing: VOTRIENT may impair wound healing.

Hypothyroidism:  Hypothyroidism has been reported in the RCC and STS clinical trials.

Proteinuria: Proteinuria was reported as an adverse reaction in the RCC and STS clinical trials. Urine protein should be monitored and VOTRIENT treatment interrupted if 24-hour protein = 3 grams. VOTRIENT treatment should be discontinued 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.

Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other anti-cancer agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in paediatric patients.

Pregnancy Category D: VOTRIENT can cause foetal 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.

Diarrhoea: Diarrhoea occurred frequently and was predominantly mild to moderate in severity in both the RCC and STS clinical trials.  

Lipase Elevations: Increases in lipase values were observed in a single arm RCC trial. Clinical pancreatitis was observed in the RCC trials.

Pneumothorax: Pneumothorax was reported in the RCC and STS clinical trials.

Drug Interactions: Coadministration of pazopanib with strongCYP3A4 inhibitors or CYP3A4 inducers should be avoided.

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

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit www.gsk.com.

[i] Colombo N, Peiretti M, Parma G et al. Ann Oncol 2010;21 Suppl 5:v23–v30

[ii] Herzog TJ & Pothuri B Nat Clin Pract Oncol 2006;3:604–611

[iii] Baldwin LA, Huang B, Miller RW et al. Obstet Gynecol 2012;120:612–618

Cautionary statement regarding forward-looking statements
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 Item 3.D 'Risk factors' in the company's Annual Report on Form 20-F for 2012.