Pivotal Phase III Trial of Novartis Drug Afinitor® Met Primary Endpoint in Study of Patients With Advanced Pancreatic Neuroendocrine Tumors

EAST HANOVER, N.J., June 3 /PRNewswire/ -- Novartis Pharmaceuticals Corporation ("Novartis") announced today that a Phase III study of Afinitor® (everolimus) tablets plus best supportive care met its primary endpoint, showing the drug significantly extended progression-free survival, or time without tumor growth, in patients with advanced pancreatic neuroendocrine tumors (NET). The study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), is part of the largest clinical trial program of its kind.

Everolimus is approved under the trade name Afinitor® (everolimus) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.

Pancreatic NET can grow aggressively and at time of diagnosis nearly 60% of all patients have advanced disease, meaning the cancer has spread to other parts of the body and has become more difficult to treat(1),(2). The median survival rate for patients with advanced pancreatic NET is 17 months(2). Currently, surgery and chemotherapy are the only approved treatment options for patients with advanced pancreatic NET(1).

"Everolimus was developed to inhibit the mTOR protein, which is a critical target in treating various cancers, including NET. Results from RADIANT-3 demonstrate that everolimus has the potential to become an important treatment option for patients with advanced pancreatic NET, where there is a major unmet need," said Herve Hoppenot, President, Novartis Oncology. "These study results will serve as the basis of worldwide regulatory filings for everolimus and bring us one step closer to our goal of offering these patients a new therapy."

Full results from the RADIANT-3 study will be submitted for presentation at the European Society for Medical Oncology annual meeting taking place in Milan, Italy in October. Additionally, worldwide regulatory filings are planned for 2010.

Study details

RADIANT-3 is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus best supportive care versus placebo plus best supportive care in 410 patients with advanced pancreatic NET, also known as islet cell tumors. Patients who met the study's entry criteria were randomized 1:1 to receive either daily everolimus (10 mg) or daily placebo orally.

The primary endpoint of RADIANT-3 is progression-free survival. Secondary endpoints include safety, objective response rate and overall survival.

About neuroendocrine tumors

Neuroendocrine tumors arise from cells that can produce and secrete a variety of hormones that regulate bodily functions. There are many types of NET that can occur throughout the body; however, most are found in the gastrointestinal tract, pancreas and lungs(3). Because NET are relatively rare, there is no routine screening and patients often experience delays of five to seven years before receiving an accurate diagnosis(3),(4). As a result of this, patients with NET often have advanced disease when diagnosed(3). Although considered a rare cancer, the incidence of NET is increasing dramatically, having quadrupled in the past 30 years(3).

About everolimus

In the US, everolimus is approved under the trade name Afinitor® (everolimus) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In the European Union (EU), Afinitor is approved for the treatment of patients with advanced RCC whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy.

In the US, everolimus is available in different dosage strengths under the trade name Zortress® for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. In the EU, everolimus is available in different dosage strengths under the trade name Certican® for the prevention of organ rejection in heart and kidney transplant recipients.

With once-daily dosing, everolimus works by targeting mTOR in cancer cells, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism.

As an investigational compound, the safety and efficacy profile of everolimus has not yet been established in NET. Access to everolimus for NET has been carefully controlled and monitored in clinical trials designed to better understand the potential benefits and risks of the compound. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for NET anywhere in the world.

Afinitor (everolimus) tablets important safety information

Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives or to any of the excipients. Potentially serious adverse reactions to Afinitor include non-infectious pneumonitis and infections, for which patients should be monitored carefully and treated as needed. In addition, non-infectious pneumonitis may require temporary dose reduction and/or interruption or discontinuation. Patients with systemic invasive fungal infections should not receive Afinitor. Oral ulceration is a common side effect of Afinitor. Renal function, blood glucose, lipids and hematological parameters should be evaluated prior to the start of therapy with Afinitor and periodically thereafter. Strong or moderate CYP3A4 or P-glycoprotein inhibitors should be avoided. An increase in the dose of Afinitor is recommended when co-administered with a strong CYP3A4 inducer.  Live vaccinations and close contact with those who have received live vaccines should be avoided by patients taking Afinitor. Afinitor should not be used in patients with severe hepatic impairment. Afinitor may cause fetal harm in pregnant women.

The most common adverse reactions, irrespective of causality (incidence greater than or equal to 30%), were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%) and diarrhea (30%). The most common grade 3/4 adverse reactions, irrespective of causality (incidence greater than or equal to 3%), were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%) and asthenia (3%). The most common laboratory abnormalities (incidence greater than or equal to 50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%) and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence greater than or equal to 3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%) and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed in patients receiving Afinitor.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "to be submitted," "planned," "can," "potential," "will," "goal," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Afinitor or regarding potential future revenues from Afinitor. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Afinitor to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Afinitor will be approved for any additional indications or labeling in any market. Nor can there be any guarantee that Afinitor will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Afinitor could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2009, the Group's continuing operations achieved net sales of USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.

References

1. National Library of Medicine and the National Institutes of Health. Pancreatic islet cell tumor. Available at http://www.nlm.nih.gov/medlineplus/ency/article/000393.htm. Accessed May 2010.
2. Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc 19: 1727-1733, 2008.
3. Yao, et al. One Hundred Years After "Carcinoid:" Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18.
4. Modlin, et al. Priorities for Improving the Management of Gasteroenteropancreatic Neuroendocrine Tumors. J Natl Cancer Inst 2008;100:1282-1289.

SOURCE Novartis Pharmaceuticals Corporation

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