GlaxoSmithKline’s pazopanib improved progression free survival in adults with certain soft tissue sarcomas

Results of the PALETTE (PAzopanib ExpLorEd in SofT-Tissue Sarcoma) study presented at the 2011 Annual Meeting of the American Society for Clinical Oncology demonstrated a statistically significant improvement in the time to first occurrence of tumour progression or death (progression free survival or PFS) for study patients treated with the multi-tyrosine kinase inhibitor pazopanib, compared to placebo. PALETTE is a randomised, double-blind, placebo controlled Phase III trial in patients with metastatic soft tissue sarcomas (excluding gastrointestinal stromal tumours and adipocytic sarcomas) and was jointly conducted by GlaxoSmithKline and the European Organisation for Research and Treatment of Cancer (EORTC) in collaboration with cancer centres across the world. Use of pazopanib to treat soft tissue sarcomas is investigational and subject to evaluation of benefits and risks by regulatory authorities before being made available for that use.

369 adults with certain metastatic soft tissue sarcomas whose disease had progressed despite treatment with chemotherapy were randomly assigned on a 2 to 1 basis to pazopanib or placebo. The study showed a 69% reduction in the risk of progression or death in patients who received pazopanib compared to those who received placebo (hazard ratio 0.31 with 95% CI 0.24 to 0.40, p<0.0001). The median PFS for patients receiving pazopanib was 4.6 months compared 1.5 months for those receiving placebo (p<0.0001). The PFS benefit for pazopanib seen in the overall population was consistent across three pre-specified subgroups: leiomyosarcoma, synovial sarcoma, and a subgroup of various histologic sarcoma subtypes. Overall survival at the interim analysis was not statistically significant (median 11.9 months pazopanib, 10.4 months placebo; p=0.1782).

“We were motivated to investigate the effects of pazopanib in patients with certain soft tissue sarcomas based on the potential role of angiogenesis in these tumours and the need for new agents that could possibly delay progression of the disease,“ said Lini Pandite, Vice President and Medicine Development Leader.

In this trial, commonly occurring toxicities (>20%) for pazopanib and placebo respectively were: fatigue (65%;49%), diarrhea (58%;16%), nausea (54(%), weight loss (48%;20%), hypertension (41%, 7%), loss of appetite (40%;20%). Grade 3-4 toxicities for pazopanib and placebo occurring on therapy were: fatigue (13%;6%), elevations in the liver enzyme ALT (10%;3%), diarrhea (5%;1%), nausea (3%;2%), hypertension (28%;3%), decreased appetite (6%;0). Cardiac dysfunction was reported in 9% of the pazopanib group and 4% of the placebo group. Venous thromboembolic events were reported in 5% of the pazopanib group and 2% of placebo group. Pneumothorax was reported in 3% of pazopanib patients and 0% of placebo patients. Fatal adverse events occurring on therapy were reported in 5% of the placebo group and 3% of the pazopanib group with one death attributed to pazopanib by the investigator.

About Soft Tissue Sarcoma (STS)

STS is a cancer of the connective tissues: nerves, muscles, joints, bone, blood vessels. There are more than 50 distinct subtypes of soft tissue sarcoma with varying prognosis and response to treatment. [i]

STS is a rare disease, accounting for about 1% of adult cancer cases in the US. In Europe, the incidence is estimated to be about 4 out of 100,000 new cancer diagnoses each year. [ii]

About EuropeanOrganisation for Research and Treatment of Cancer (EORTC)

Founded in 1962, EORTC is a nonprofit international cancer research organization under Belgian law. The EORTC has the mission to develop, conduct, coordinate and stimulate translational and clinical research in Europe to improve the management of cancer and related problems by increasing survival but also patient quality of life.

The EORTC is both multinational and multidisciplinary, and the EORTC Network comprises over 300 hospitals and cancer centers in over 30 countries which include some 2,500 collaborators from all disciplines involved in cancer treatment and research.

About pazopanib

Votrient™ (pazopanib) is an oral medication and is approved for the treatment of advanced renal cell carcinoma in adults in the United States, the European Union, Russia, Brazil, South Korea and other countries across the world.

Votrient is targeted cancer medicine that may block the growth of cancer cells. It is important to note that Votrient may also harm healthy cells. Votrient works to inhibit the development and growth of new blood vessels and to shrink or slow the growth of cancer by inhibiting proteins called tyrosine kinases.

US Important Safety Information for Votrient in Advanced Renal Cell Carcinoma

WARNING: HEPATOTOXICITY

Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions”, Section 5.1, in complete Prescribing Information.

Hepatic Effects: Patients with pre-existing hepatic impairment should use Votrient with caution. Treatment with Votrient is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). 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 been observed with Votrient. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhytmics 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.

Hemorrhagic Events: Fatal hemorrhagic events have been reported (all grades [16%] and Grades 3 to 5 [2%]). Votrient has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of Votrient, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events.

Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula.

Hypertension: Hypertension has been observed. Hypertension was observed in 47% of patients with RCC treated with Votrient. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating Votrient. Monitor for hypertension and treat as needed. If hypertension persists despite antihypertensive therapy, the dose of Votrient may be reduced or discontinued as appropriate.

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

Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria.

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

Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of Votrient when administering with strong CYP3A4 inhibitors.

CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid Votrient.

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

Adverse Reactions: The most common adverse reactions (>20%) for Votrient versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%).

Laboratory abnormalities occurring in >10% of patients and more commonly (>5%)in the Votrient arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs.19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose 17% vs. 3%); and leucopenia (37% vs. 6%), neutropenia 34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%).

Votrient has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%).

Please see full US Prescribing Information for Votrient, including BOXED WARNING at www.gsk.com.