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Title: Study Compares Doxil/Caelyx (Doxorubicin HCL Liposome Injection) to Doxorubicin for First-Line Treatment of Metastatic Breast Cancer

"Study Compares Doxil/Caelyx (Doxorubicin HCL Liposome Injection) to Doxorubicin for First-Line Treatment of Metastatic Breast Cancer"

BRIDGEWATER, NJ -- May 20, 2004 -- Results from a new study comparing Doxil to conventional doxorubicin in first-line treatment of metastatic breast cancer were published in the March 2004 issue of Annals of Oncology.(1) This phase III study of 509 women with metastatic breast cancer found: * Progression-free survival (PFS) for patients treated with Doxil was not significantly different compared to those treated with doxorubicin: 6.9 months for Doxil compared to 7.8 months for doxorubicin. * Overall survival was comparable with both treatments: 21 months for Doxil vs. 22 months for doxorubicin. * The overall incidence of cardiotoxicity was significantly higher with doxorubicin (48 patients) than with Doxil (10 patients). No Doxil treated patient within this group developed signs or symptoms of congestive heart failure (CHF), whereas ten doxorubicin patients did. "While more research is needed, these data may be particularly relevant for patients with metastatic breast cancer who are at increased cardiac risk, such as the elderly, or patients with specific cardiac risk factors," observed lead researcher Mary E. O'Brien, M.D., F.R.C.P., who is affiliated with Royal Marsden Hospital in Sutton, Surrey, U.K. The study: * Was an open-label, multi-center study assessing whether Doxil was comparable to conventional doxorubicin with respect to PFS, and to compare the cardiac safety profile of the two agents. * Was conducted at 68 international sites (North America, Central America, South America, Europe, Israel, South Africa, Australia and New Zealand). * Involved women with metastatic breast cancer (stage IIIB or IV) who were randomized to receive either Doxil (50 mg/m2 every four weeks, n = 254) or conventional doxorubicin (60 mg/m2 every three weeks, n = 255). Cardiac event rates were assessed by reductions in left ventricular ejection fraction (LVEF, defined as the proportion of the volume of blood in the left ventricle that is ejected when the heart pumps), as a function of cumulative anthracycline dose. At cumulative doses at or above 450 mg/m2, a 7-fold greater mean percent decrease in LVEF was observed with doxorubicin versus Doxil (-17.2 percent versus -2.3 percent; mean percent change from baseline in LVEF in doxorubicin-treated patients and Doxil-treated patients, respectively). Ten Doxil-treated patients developed protocol-defined cardiac events, compared to 48 doxorubicin-treated patients. The increase in risk of developing cardiotoxicity while on treatment with doxorubicin was observed in all subgroups analyzed, including those at high risk for developing CHF. In the subgroup that received prior adjuvant anthracycline therapy, 66 of 78 patients were evaluated at time of publication. One patient treated with Doxil developed a protocol-defined cardiac event compared to 11 patients treated with doxorubicin. Of the 410 patients (209 Doxil; 201 doxorubicin) with measurable disease, overall response rates (complete plus partial) were similar for Doxil (33 percent) and doxorubicin-treated patients (38 percent). The median duration of response was comparable between the two groups: 7.3 months for Doxil- treated patients and 7.1 months for doxorubicin-treated patients. In both groups, 24 percent of patients discontinued therapy due to toxicity (adverse event or cardiac toxicity). Among doxorubicin-treated patients, 24 (9.4 percent) discontinued due to an adverse event and 36 (14.1 percent) discontinued due to cardiac toxicity; among Doxil-treated patients, the corresponding numbers were 56 (22.0 percent) and 6 (2.4 percent). Alopecia (hair loss; overall: 66 percent vs. 20 percent; pronounced: 54 percent vs. 7 percent), nausea (53 percent vs. 37 percent), vomiting (31 percent vs. 19 percent) and neutropenia (low white blood cell count; 10 percent vs. 4 percent) were more often associated with doxorubicin than with Doxil. Hand-foot syndrome (also known as palmar-plantar erythrodysesthesia [PPE] 48 percent vs. 2 percent), stomatitis (22 percent vs. 15 percent), and mucositis (23 percent vs. 13 percent) were more often associated with Doxil than with doxorubicin. About Breast Cancer and Doxil The National Cancer Institute estimates that close to 40,000 American women died from breast cancer in 2003 and that there were more than 211,000 new cases of breast cancer diagnosed in the U.S. in 2003. After skin cancer, breast cancer is the most common form of cancer among women.(2) Doxil is indicated for the treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel- and platinum- based chemotherapy regimens. Refractory disease is defined as disease that has progressed while on treatment, or within six months of completing treatment. Doxil is also indicated for the treatment of AIDS-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy. These indications are based on objective tumor response rates. No results are available from controlled studies that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms or increased survival. Doxil is an advanced formulation of conventional doxorubicin. Specifically, a layer of fatty bubbles, called liposomes, encapsulates the doxorubicin. Through a process known as pegylation, the liposomes are coated with a layer of hair-like strands made from methoxypolyethylene glycol (MPEG). Pegylation helps protect the medication from recognition and destruction by the immune system, resulting in it circulating in the blood for a longer period of time than conventional doxorubicin. Experience with Doxil at high cumulative doses is too limited to have established its effects on the myocardium. Therefore, it should be assumed that Doxil will have myocardial toxicity similar to conventional formulations of doxorubicin HCl. Doxil should be administered to patients with a history of cardiovascular disease only when the benefit outweighs the risk. Acute infusion-associated reactions have occurred in up to 10 percent of patients treated with Doxil. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Severe myelosuppression may occur. Dosage should be reduced in patients with impaired hepatic function. Accidental substitution of Doxil for doxorubicin HCl has resulted in severe side effects. DO NOT SUBSTITUTE. The use of Doxil should be limited to physicians experienced in the use of cancer chemotherapeutic agents. In clinical studies, the most common side effects reported with Doxil therapy included reduced red blood cell count (anemia), reduced white blood cell count (neutropenia), nausea, hand-foot syndrome, mouth sores (stomatitis), weakness, vomiting, rash, mild hair loss, constipation, appetite loss, diarrhea, and tiredness. Some patients experienced infusion-related reactions and skin reactions. Hand-foot syndrome, also known as PPE, is characterized by symptoms of swelling, pain, redness and, for some patients, peeling of the skin on the hands and feet; in 17 percent of patients, these symptoms were moderate to severe. In some patients, heart-related side effects were reported, some of which were severe. Due to the serious, potentially permanent effects of some of these events, including the potential for bone marrow suppression, close monitoring is necessary. Doxil is marketed as Doxil in the United States by Tibotec Therapeutics, a division of Ortho Biotech Products, L.P., and in Israel by Janssen-Cilag. Schering-Plough Pharmaceuticals, under a licensing agreement, has exclusive rights to market this medication as CAELYX(R) throughout the rest of the world. For more information about Doxil, please visit http://www.Doxil.com. Full prescribing information for Doxil is available at http://www.Doxil.com/05_shared_pages/01_prescribing_info.html.com. References: (1) O'Brien MER, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase 3 trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Annals of Oncology 2004; 15: 440-449. (2) National Cancer Institute. What You Need to Know about Breast Cancer; (http://www.cancer.gov/cancerinfo/wyntk/breast). SOURCE: Tibotec Therapeutics

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