2) Combination with bevacizumab (Avastin)

The pivotal phase III study compared bevacizumab in combination with interferon alfa-2a (N=327) to placebo plus interferon alfa-2a (N=322) as first-line therapy of nephrectomised patients with advanced and/or metastatic rena; cell carcinoma.
Table 1: Efficacy results for study BO17705
Parameter

(median value)
 Pbo + IFN N = 322
 Bv + IFN N = 327
 Hazard Ratioα
 p-value
 
Overall survival
 21.3 mo.
 23.3 mo.
 0.91

(0.76 – 1.10)
 p = 0.3360β
 
Progression-free survival
 5.5 mo.
 10.2 mo.
 0.75

(0.64 – 0.88)
 p < 0.0004β
 
Overall response rateγ
 12.5 %
 32.4 %
 19.9
 p < 0.0001δ
α - determined with a 95 % CI. For ORR, a difference in rates between study arms is given instead.

β - p-value was obtained using Log-Rank Test

γ - populations for reference are those patients with measurable disease at baseline [ITT N = 289 / 306]

δ - p-value was obtained using χ2 Test

Surgically Resected Malignant Melanoma

The efficacy of Roferon-A in patients with primary cutaneous melanoma thicker than 1.5 mm and without clinically detectable node metastasis was assessed in a large randomised study involving 253 patients receiving Roferon-A at a dose of 3 MIU three times a week for 18 months, compared with 246 untreated controls. After a median follow-up of 4.4 years a significant extension of relapse-free interval (p=0.035) but no statistically significant difference in overall survival (p=0.059) in Roferon-A treated patients compared with controls have been shown. The overall treatment effect was a 25% reduction in the risk of relapse.

5.2 Pharmacokinetic properties

 The serum concentrations of interferon alfa-2a reflected a large intersubject variation in both healthy volunteers and patients with disseminated cancer. The pharmacokinetics of Roferon-A in animals (monkey, dog and mouse) were similar to those seen in man. The pharmacokinetics of Roferon-A in man were linear over a 3 million to 198 million IU dose range. In healthy man, interferon alfa-2a exhibited an elimination half-life of 3.7 - 8.5 hours (mean: 5.1 hours), a volume of distribution at steady state of 0.223 - 0.748 l/kg (mean: 0.4 l/kg) and a total body clearance of 2.14 - 3.62 ml/min/kg (mean: 2.79 ml/min/kg) after a 36 million IU intravenous infusion. After intramuscular administration of 36 million IU, peak serum concentrations ranged from 1500 to 2580 pg/ml (mean: 2020 pg/ml) at a mean time to peak of 3.8 hours, and after subcutaneous administration of 36 million IU from 1250 to 2320 pg/ml (mean: 1730 pg/ml) at a mean time to peak of 7.3 hours.

The apparent fraction of the dose absorbed after intramuscular or subcutaneous injection is greater than 80%.

The pharmacokinetics of interferon alfa-2a after single intramuscular doses to patients with disseminated cancer and chronic hepatitis B were similar to those found in healthy volunteers. Dose-proportional increases in serum concentrations were observed after single doses up to 198 million IU. There were no changes in the distribution or elimination of interferon alfa-2a during twice daily (0.5 - 36 million IU), once da