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Title: Hycamtin(R) (Topotecan HCl) Indication Expanded To Include Treatment of Cervical Cancer in Combination With Chemotherapy

"Hycamtin(R) (Topotecan HCl) Indication Expanded To Include Treatment of Cervical Cancer in Combination With Chemotherapy"

Of more than 40 regimens investigated1 Hycamtin® is the first to provide additional survival benefit beyond the current standard treatment LONDON, UK -- December 1, 2006 -- GlaxoSmithKline plc announced today that the European Medicines Agency (EMEA) has granted Marketing Authorisation for Hycamtin (topotecan HCl) in combination with cisplatin, for the treatment of patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. The indication also includes the following qualifying statement that 'patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination'. The expanded indication is based on phase 3 results that demonstrate a survival advantage by using Hycamtin (0.75mg/m2 days 1-3) in combination with cisplatin (50mg/m2 day 1), compared to cisplatin (50 mg/m2) alone. The marketing authorisation follows a positive opinion in October 2006 by the European Committee for Human Medicinal Products (CHMP) for Hycamtin. "Advanced cervical cancer often has a very poor prognosis, even with current treatments, so new treatment options such as Hycamtin, represent welcome treatment advances for the many women facing this disease every year," said Professor Hani Gabra, Professor of Medical Oncology at the Hammersmith Campus of Imperial College London. "For patients with so few other options it is an encouraging step forward in the management of advanced/recurrent cervical cancer." The randomised, multicentre trial was designed and conducted by the Gynaecologic Oncology Group (GOG) in the USand results were previously published in the Journal of Clinical Oncology.1 The study found that Hycamtin, in combination with cisplatin, was more effective in treating cervical cancers which were not appropriate for curative treatment with surgery and/or radiation therapy, than cisplatin alone. Andrew Witty, President of European Pharmaceuticals at GSK said, "GSK is focussed on closing in on cancer from all sides to ensure that we are not only helping the women of today who have cervical cancer but also those who may be at risk in the future. More than 40 drug regimens have been tested against incurable cervical cancer, despite this there is no approved therapy. The combination of Hycamtin and cisplatin is now the only approved therapy representing a significant advance." About the GOG Phase 3 Trial The trial enrolled women with measurable, histologically-proven stage IVB, recurrent or persistent carcinoma of the cervix, who had recovered from the effects of prior surgery, radiation or chemoradiation. Patients were originally randomised into three arms: single-agent cisplatin (n=146, 50 mg/m[², every 21 days), Hycamtin plus cisplatin (n=147, Hycamtin 0.75 mg/m2, day 1-3 plus cisplatin 50 mg/m² day 1 every 21 days), or MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin every 28 days). However, the MVAC arm was closed after 64 patients were enrolled, due to excessive toxicity.2

The study showed a statistically significant improvement in overall survival for Hycamtin plus cisplatin arm (two-sided log-rank P=0.033). Median survival for Hycamtin plus cisplatin was 9.4 months when compared to 6.5 months for cisplatin alone.2 This GOG study was led by Dr. Harry J. Long III, Professor of Oncology at Mayo Clinic College of Medicine in Rochester, Minnesota, USA.

Toxicity of the Hycamtin plus cisplatin combination was predictable and manageable. The most common dose-limiting toxicity was myelosuppression. Major haematological adverse events (Grade 3 and 4) were more frequent in the combination arm than in the single-agent arm and included neutropenia (74% vs. 2%), thrombocytopenia (33% vs. 3%), infection-febrile neutropenia (19% vs. 8%), respectively. The most common non-haematological adverse events reported were constitutional*, gastrointestinal, pain and metabolic toxicities.

Cervical Cancer Facts
· · Each year, cervical cancer is diagnosed in 500,000 women and an estimated 270,000 women die from the disease worldwide. 3

· · Across Europe, there are around 60,000 reported cervical cancer cases and an estimated 30,000 deaths occur each year from cervical cancer 3,4

· · Across Europe, every 18 minutes, a woman dies of cervical cancer. 3

· · Overall, cervical cancer is the second most prevalent cancer in women aged under 45 years worldwide. 3

· · 80% of deaths from cervical cancer occur in the developing world where it remains the leading cause of cancer death in women. 5

About Hycamtin
Hycamtin is currently marketed in the EU by GlaxoSmithKline. It belongs to a class of drugs known as the topoisomerase I (topo-I) inhibitors. Topo-I is a naturally produced protein essential for cell division in both normal and cancer cells. Interaction between topo-I and Hycamtin results in permanent damage to the cell's genetic material and the death of dividing cancer cells. Hycamtin was originally approved for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent therapy. It was later also approved for the treatment of small cell lung cancer disease for those whom re-treatment with the first-line chemotherapy is not considered appropriate.

Important Safety Information
Hycamtin can suppress the body's ability to produce disease fighting white blood cells, a condition known as neutropenia. In addition, the number of platelets (clotting cells) can decrease (thrombocytopenia). Generally, Hycamtin has a mild to moderate non-haematological toxicity profile. Side effects include nausea, vomiting, diarrhoea and hair loss (alopecia).

REFERENCES:
1. DiSaia P, Creasman W. Clinical Gynecologic Oncology 5th ed. 51-106 St. LouisMo: Mosby-Year Book Inc. 1997
2. Long HJ. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: A Gynecologic Oncology Group Study. J Clin Oncol. 2005;23:4626-4633.
3. Ferlay J, Bray F, Pisani P, Parkin DM. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancerbase No. 5. Version 2.0, IARCPress, Lyon, 2004. Available at: www.depdb.iarc.fr/globocan/GLOBOframe.htm
4. www.who.int/vaccine_research/diseases/hpv/en
5. Bosch FX et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC). Study Group J Natl Cancer Inst 1995; 87: 796—802

SOURCE: GlaxoSmithKline plc

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