Phase II, randomized, multicenter, comparative study of peginterferon-alpha-2a (40 kD) (Pegasys) versus interferon alpha-2a (Roferon-A) in patients with treatment-naïve, chronic-phase chronic myelogenous leukemia.

The efficacy and safety of peginterferon-alpha-2a (40 kD) (PEG-IFNalpha-2a), 450 microg once weekly, versus IFNalpha-2a, 9 MIU once daily, for 12 months, was evaluated in a Phase II study in IFN-naïve patients with chronic-phase, Philadelphia-chromosome-positive CML. At the end of the treatment, complete hematological response was observed in 66.2% (47/71) and 45.2% (33/73) of the PEG-IFNalpha-2a group and IFNalpha-2a groups, respectively (p = 0.009), and major cytogenetic response occurred in 35.2% and 17.8%, respectively (p = 0.016). PEG-IFNalpha-2a was at least as effective as IFNalpha-2a overall, including progression-free survival at the end of treatment, and overall survival after 30 months of follow-up. Adverse events necessitated fewer withdrawals but more dose adjustments in the PEG-IFNalpha-2a group compared with the IFNalpha-2a group (11%versus 23%, and 84.5%versus 65.8%, respectively). In conclusion, PEG-IFNalpha-2a (40 kD), 450 microg once weekly, compared with IFNalpha-2a, 9 MIU once daily, resulted in higher rates of hematologic and cytogenetic response and greater overall survival.

Long-term safety of intravenous ibandronic acid for up to 4 years in metastatic breast cancer: an open-label trial.

BACKGROUND AND OBJECTIVE: Despite their widespread use in metastatic bone disease, some bisphosphonate drugs are associated with adverse events (AEs), particularly renal toxicity, adding to treatment burdens and increasing healthcare costs. Ibandronic acid is a single-nitrogen bisphosphonate with high efficacy against bone events and metastatic bone pain, and a renal safety profile compar- able to that of placebo. In this study, the safety of ibandronic acid was examined over a period of 4 years. PATIENTS AND METHODS: During an initial 96-week period, breast cancer patients with bone metastases were randomised in double-blind fashion to placebo or ibandronic acid 6mg administered by intravenous infusion over 1-2 hours every 3-4 weeks as part of a previously reported phase III trial (MF 4265 study). All patients completing the phase III trial were offered open-label active treatment for a further 96 weeks (extension phase). A total of 62 patients received ibandronic acid 6mg in this extension phase and were classified according to their initial treatment (placebo/ibandronic acid 6mg [placebo/6mg] and ibandronic acid 6mg/ibandronic acid 6mg [6mg/6mg] groups). Safety was assessed by AE reports and clinical laboratory evaluations. RESULTS: During the 4-year study, most patients experienced at least one AE, with malignancy progression being most commonly reported. However, fewer treatment-related AEs were reported in the extension phase (placebo/6mg: 6.3% [1/16]; 6mg/6mg: 13.0% [6/46]) than in the initial phase of the study (placebo: 56.3% [9/16]; 6mg: 67.4% [31/46]). Serious AEs were mainly due to malignancy progression. There were no clinically relevant renal AEs, and in both groups, serum creatinine levels were similar for up to 4 years. CONCLUSION: This 96-week open-label safety extension of a phase III, placebo-controlled trial demonstrates that long-term use of intravenous ibandronic acid is well tolerated.

Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer.

The objective of this study is to assess the effect of oral ibandronate on bone pain and quality of life in women with metastatic bone disease from breast cancer. In two double-blind, placebo-controlled studies, 564 patients were randomised to receive oral ibandronate, 50mg once daily, or placebo for up to 96 weeks. Throughout the studies, we assessed bone pain (on a 5-point scale from 0=none to 4=intolerable), analgesic use (7-point scale) and quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 [EORTC QLQ-C30], 100-point scale). Oral ibandronate significantly reduced and maintained bone-pain scores below baseline throughout the 96-week study period (at endpoint, -0.1 vs +0.2, P=0.001 vs placebo). Analgesic use increased in both groups; however, the increase was significantly less in the ibandronate group (0.60 vs 0.85, P=0.019). Although quality of life deteriorated during the study, the decrease in quality of life was significantly lower with ibandronate therapy (-8.3 vs -26.8, P=0.032). Drug-related adverse events were generally minor and as expected with oral bisphosphonates. Oral ibandronate had beneficial effects on bone pain and quality of life and was well tolerated. These results suggest that this treatment is of considerable clinical value as a co-analgesic to patients with painful bone metastases.

Review of ibandronate in the treatment of metastatic bone disease: experience from phase III trials.

BACKGROUND: Metastatic bone disease is a serious clinical problem in patients with advanced cancer. Bisphosphonates inhibit the activity of osteoclasts and are the treatment of choice for bone metastases. OBJECTIVE: This article reviews the efficacy and safety data from Phase III trials of ibandronate in metastatic bone disease. METHODS: Phase III data (available as of June 2004) for ibandronate were reviewed. Literature searches using the MEDLINE database and abstracts from scientific meetings were used to obtain data from Phase III trials of ibandronate. RESULTS: Compared with placebo, patients with bone metastases from breast cancer receiving IV ibandronate (6 mg infused over 1-2 hours every 3-4 weeks) or oral ibandronate (50 mg/d for up to 96 weeks) had a statistically significant reduction in skeletal complications, as measured by the Skeletal Morbidity Period Rate (P = 0.004 vs placebo). Multivariate Poisson regression analysis of the data showed that the risk of a new bone event was reduced by 40% with IV ibandronate 6 mg and by 38% with oral ibandronate 50 mg, compared with placebo (P < or = 0.003). Both formulations also reduced bone pain below baseline levels over 2 years (P < or = 0.001 vs placebo). IV and oral ibandronate were well tolerated, with adverse-event profiles comparable to placebo and no significant renal toxicity. CONCLUSIONS: IV and oral ibandronate provide meaningful clinical benefits in patients with bone metastases from breast cancer. Both formulations reduce the risk of skeletal events and provide sustained relief from metastatic bone pain. With its favorable efficacy and safety profile, and the added convenience of the oral formulation, ibandronate provides improved treatment options for managing metastatic bone disease.

Preclinical and clinical efficacy of the bisphosphonate ibandronate in cancer treatment.

Bisphosphonates, like ibandronate (Bondronat), represent the mainstay of treatment for metastatic bone disease. Ibandronate selectively binds to bone mineral and prevents osteoclast-mediated skeletal destruction. This review describes the preclinical and clinical profiles of ibandronate for treatment of cancer metastatic to bone. In preclinical studies ibandronate reduced metastatic processes and tumor growth, induced tumor cell apoptosis, decreased bone pain, and enhanced biomechanical indices. Skeletal destruction was completely prevented with ibandronate, and this directly correlated with histomorphometry and markers of bone turnover. Ibandronate efficacy in combination with anti-cancer therapies is discussed. Preclinical studies demonstrated that ibandronate does not compromise safety, including renal health. Intravenous and oral ibandronate had comparable efficacy in three Phase III clinical trials. Ibandronate achieved significant risk reductions in the incidence of skeletal-related events and bone pain. In additional clinical studies, ibandronate reduced markers of bone turnover. Furthermore, loading-dose ibandronate rapidly reduced bone pain in Phase II trials. Adjuvant trials are ongoing. The clinical safety profile (including a 4-year follow-up study) has demonstrated renal health is maintained with ibandronate. Overall, ibandronate preserves skeletal integrity, has a favorable safety profile, maintains renal function, and can rapidly reduce and maintain bone pain below baseline levels in patients with cancer metastatic to bone.

Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma.

PURPOSE: A pegylated interferon, peginterferon alfa-2a (PEG-IFNalpha-2a; 40 kd), has the potential for improved tumor response and survival with lower toxicity than IFNalpha. This open-label, randomized study evaluated the safety, tolerability, and efficacy of subcutaneous PEG-IFNalpha-2a in patients with metastatic malignant melanoma (stage IV American Joint Committee on Cancer staging system). PATIENTS AND METHODS: PEG-IFNalpha-2a was administered subcutaneously at 180 (n = 48), 360 (n = 53), or 450 mug (n = 49) once weekly for 24 weeks, with maintenance therapy for responders. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS: The major response rate (CR or PR) was 6% in the 180-mug group (CR, 2%; PR, 4%), 8% in the 360-mug group (CR, 2%; PR, 6%), and 12% in the 450-mug group (CR, 6%; PR, 6%). The times to achieve a major response, duration of major response, rate of disease progression, and 12-month survival were similar between groups, although overall median survival was significantly different among the three groups (P = .0136). More patients required dose adjustment for safety reasons in the higher dose groups, but PEG-IFNalpha-2a was generally well tolerated, with few withdrawals because of adverse events (6%, 19%, and 16% in the 180-, 360-, and 450-mug groups, respectively). The most common adverse events were fatigue, pyrexia, and nausea. CONCLUSION: PEG-IFNalpha-2a at doses up to 450 mug once weekly has shown good tolerability and similar efficacy to conventional IFNalpha and monochemotherapy in stage IV metastatic melanoma.