Oral Hycamtin(R) Clinically Active in the Treatment of Small

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Cell and Non-Small Cell Lung Cancer

http://www.medicalnewstoday.com/medical ... wsid=24663

19 May 2005

Results from two new, investigational Phase III clinical trials showed that oral Hycamtin® was clinically active in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both studies were presented here this week at the annual meeting of the American Society of Clinical Oncology (ASCO) (Abstracts 7003 and 7017). At this time, oral Hycamtin does not have regulatory approval in any country for use in any indication.

Results from one trial showed Hycamtin to be one of the first oral chemotherapeutic agents to demonstrate clinical activity in a phase III study of patients with relapsed stage III/IV NSCLC. Additionally, results from one of the largest studies conducted in extensive SCLC disease showed that oral Hycamtin, combined with cisplatin, demonstrated clinical activity and tolerability similar to IV etoposide/cisplatin, the standard of care.

"Oral Hycamtin may be a convenient therapy for patients who might otherwise choose best supportive care over intravenous chemotherapy -- either because they reside a long distance from the hospital or because they prefer to live their remaining few weeks of life at home," said study investigator, John Eckardt, M.D., director of the clinical research program at the Center for Cancer Care and Research, St. Louis, Missouri. "Results from these two investigational studies suggest that oral Hycamtin may one day be an important alternative for these patients."

Study Shows Oral Hycamtin Clinically Active in Relapsed NSCLC One open-label, phase III trial studied the risk/benefit profile of oral Hycamtin compared with IV docetaxel. A total of 829 previously-treated patients were recruited from 140 centers worldwide. Patients were randomized to receive either single agent oral Hycamtin 2.3 mg/m2 daily on days 1-5, every 21 days (n=414) or IV docetaxel 75 mg/m2 on day 1, every 21 days (n=415).

Results for one-year survival rate, the study's primary endpoint, were similar between groups (25.1 percent for oral Hycamtin versus 28.7 percent for IV docetaxel). With regard to differences in one-year survival between groups, Hycamtin was shown to be non-inferior to docetaxel based on the study's pre-specified non-inferiority margin. Oral Hycamtin was also similar to docetaxel in median survival (27.9 weeks versus 30.7 weeks, respectively). Nineteen patients in each group (4.6 percent) achieved a complete or partial response, and stable disease was observed in 111 patients (26.8 percent) in the oral Hycamtin group versus 148 patients (35.7 percent) in the IV docetaxel group. Patients given IV docetaxel in the study experienced significantly longer time to progression (TTP) compared to those given oral Hycamtin (Hazards Ratio 1.19 [95% CI 1.03, 1.37]; P = 0.0196). Median TTP was 13.1 weeks for patients given docetaxel versus 11.3 weeks for patients given oral Hycamtin.

"Results from this study clearly show that oral Hycamtin has activity in NSCLC and may provide another treatment option for relapsed patients with the convenience of oral therapy," said Roman Perez-Solar, M.D., Chairman, Department of Medical Oncology, Montefiore Medical Center, and Gutman Professor of Medicine, Albert Einstein College of Medicine.

A safety analysis of the treated population was conducted in 407 patients receiving oral Hycamtin and 401 patients receiving IV docetaxel. Oral Hycamtin was associated with more grade 3 thrombocytopenia, grade 3/4 anemia and overall GI symptoms while patients given IV docetaxel experienced more grade 3/4 neutropenia and neuropathy. One percent of patients given oral Hycamtin experienced sepsis compared to five percent for docetaxel. In both groups, less than 1 percent of patients died from hematologic or nonhematologic toxicity-related causes.

Study Shows Oral Hycamtin Clinically Active in SCLC

Results from a separate study of oral Hycamtin, one of the largest ever conducted in patients with extensive (disease that has spread beyond the chest) SCLC, showed that oral Hycamtin administered with IV cisplatin (TC) was similar with regard to activity and tolerability to IV etoposide/cisplatin (PE), the standard of care for first-line extensive disease SCLC.

"While Hycamtin is well established in the treatment of relapsed sensitive disease small cell lung cancer, results from this study show that Hycamtin, combined with platinum, may produce results similar to the gold standard of care while offering greater convenience with oral administration," said Dr. Eckardt.

The randomized phase III study included a total of 784 chemotherapy-naove patients with extensive disease. Patients were randomized to receive either 1.7 mg/m2 oral Hycamtin on days 1-5 and 60 mg/m2 cisplatin on day 5 (TC, n = 389) or IV etoposide 100 mg/m2 on days 1-3 and 80 mg/m2 cisplatin on day 1 (PE, n = 395).

Overall survival, the study's primary endpoint, was similar between groups, with a median survival time of 39.3 weeks in the TC group and 40.3 weeks in the PE group. One-year survival rate was 31.4 percent for both groups. Time to progression for patients in the PE group was significantly longer compared to the TC group (Hazards Ratio 1.19 [95% CI 1.03, 1.38]; P = 0.02). Median time to progression was 25.1 weeks for PE versus 24.1 weeks for TC. Overall response rate was 63 percent for patients in the TC group versus 68.9 percent for patients in the PE group. A total of 25 complete responses and 220 partial responses were observed in the TC group versus 21 complete responses and 251 partial responses in the PE group.

The median number of cycles for TC was five (range: 1-9) and six for PE (range: 1-. The initial TC dose regimen, containing Hycamtin 2.0 mg/m2/day, was reduced to 1.7 mg/m2/day due to excessive neutropenia, diarrhea, and typhilitis (a complication of neutropenia leading to ulceration of the colon). Overall, patients given PE experienced more grade 4 neutropenia and grade 3/4 vomiting, while those on TC experienced more, grade 4 thrombocytopenia, grade 3/4 anemia and diarrhea.

About Hycamtin

Hycamtin is a chemotherapeutic agent that belongs to a class of drugs known as topoisomerase I (topo-I) inhibitors. Topo-I is an enzyme essential for the replication of DNA, and therefore cell division, in both normal and cancer cells. Interaction between topo-I and Hycamtin results in damage to the cell's genetic material and the death of dividing cancer cells.

Hycamtin, in its intravenous (IV) form, is currently indicated for use in treating SCLC sensitive disease after failure of first-line chemotherapy. In clinical studies, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing at least 60 days (in the Phase III study) or at least 90 days (in the Phase II study). Hycamtin IV is also indicated for the treatment of metastatic ovarian cancer after failure of initial or subsequent chemotherapy.

For more information and full prescribing information, please visit http://www.hycamtin.com.

Important Safety Information

Hycamtin® (topotecan HCl for Injection) can suppress the body's ability to produce disease fighting white blood cells, a condition known as neutropenia. In addition, the amount of clotting cells can decrease (thrombocytopenia). Hycamtin is contraindicated in patients who have a history of hypersensitivity reactions to topotecan or any of its ingredients. Hycamtin should not be used in patients who are pregnant or breast-feeding, or in those with severe one marrow depression. The most common serious adverse event is myelosuppression.

About GlaxoSmithKline

GlaxoSmithKline (NYSE: GSK) is one of the world's leading research-based pharmaceutical and healthcare companies. GlaxoSmithKline is committed to improving the quality of human life by enabling cancer patients to do more, feel better and live longer. For more information, visit http://www.gsk.com.

GlaxoSmithKline Forward-Looking Statement

Under the safe harbor provisions of the US Private Securities Litigation Reform Act of 1995, the company cautions investors that any forward-looking statements or projections made by the company, 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 the Group's operations are described under 'Risk Factors' in the Operating and Financial Review and Prospects in the company's Annual Report on Form 20-F for 2004.

GlaxoSmithKline

http://www.hycamtin.com

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