Clinical Trial Result Information
Title of Study:
A randomized, double-blind, phase III study to evaluate the efficacy and safety of bevacizumab in combination with interferon alfa-2a (Roferon) versus interferon alfa-2a and placebo as first line treatment administered to nephrectomised patients with metastatic clear cell renal cell carcinoma.
Fast Facts:
| Protocol number: | BO17705 |
| Sponsor: | F. Hoffmann-La Roche Ltd |
| Company division: | Pharmaceutical |
| Product name: | Avastin |
| Generic name: | bevacizumab |
| Phase of development: | III |
| Therapeutic area, approved indication: | Renal Cell Cancer |
| Date of report: | 3/1/2007 |
Clinical study summary:
This was a multicenter, randomized, (2 treatment arms), double-blind study to compare the efficacy and safety of Avastin (bevacizumab) + interferon alfa-2a (IFN) versus placebo + IFN in patients with metastatic renal cell carcinoma. The interim analysis of overall survival and the final analysis of progression-free survival are reported here.
Study center(s) :
101 centers in Australia, Belgium, Czech Republic, Finland, France, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Russia, Singapore, Spain, Switzerland, Taiwan and United Kingdom.
Objectives:
Primary: To determine the efficacy of the combination of Avastin and IFN compared to placebo and IFN in patients with metastatic renal cell carcinoma (RCC), based on overall survival.
Secondary: To determine the progression-free survival, time to disease progression, time to treatment failure and objective response rates of Avastin and IFN compared to placebo and IFN; to characterize the safety profile of the combination of Avastin and IFN compared to placebo and IFN.
Methodology:
Eligible patients were randomized to one of two treatment arms: IFN 9 MIU 3 times weekly plus Avastin 10 mg/kg every 2 weeks or IFN 9 MIU 3 times weekly plus placebo every two weeks. IFN was administered for a maximum duration of 52 weeks in the absence of disease progression or major toxicity. An initial dose of <9 MIU was permitted, as long as the recommended dose was reached within the first 2 weeks of treatment. Dose reduction of IFN to 6 MIU or 3 MIU was allowed to manage grade ≥3 adverse events attributable to IFN according to NCI CTCAE v. 3.0.
Upon evidence of disease progression, all study treatments were to be discontinued permanently. In the absence of disease progression at week 57, the patient could continue with Avastin/placebo treatment until progression.
Tumor measurements/assessments were made on RECIST criteria based on CT scans, MRI scans, X-ray, bone scan, and/or clinical examination until (confirmed) evidence of disease progression. Post screening assessments were made every 8 weeks up to week 32 and every 12 weeks thereafter until disease progression.
Adverse events were recorded on an ongoing basis. Assessments including body weight, body temperature, pulse, hematology, and blood chemistry were performed pre-dose and at intervals for the duration of study therapy. Urinalysis and blood pressure were assessed prior to each Avastin/placebo infusion.
Survival follow-up was to continue until study closure. Visits were scheduled every 3 months for the first year of the survival follow-up and 6 monthly thereafter. Patients without documented disease progression were followed for progression and survival, and those with documented disease progression were followed for survival only.
Number of patients (planned/analyzed):
649 patients randomized.
Diagnosis and main criteria for inclusion:
Metastatic >50% clear cell type renal cell carcinoma; no prior systemic treatment for metastatic RCC (including neo-adjuvant therapy); age ≥18.
Test product, dose and mode of administration or test procedure:
Avastin (bevacizumab) (10mg/kg iv every two weeks) plus interferon alfa-2a (IFN) (9 MIU sc 3 times weekly).
Duration of treatment:
Until disease progression
Reference therapy, dose and mode of administration or reference procedure:
Placebo (iv administration every two weeks) plus IFN (9 MIU sc 3 times weekly).
Criteria for evaluation (efficacy, safety):
Primary: Duration of overall survival (OS).
Secondary: Progression-free survival (PFS); time to progression; time to treatment failure; overall response rate (OR); performance status (Karnofsky score).
Safety: Adverse events, laboratory tests (hematology, serum chemistry, urinalysis), vital signs, ECG.
Statistical methods:
Efficacy: 2-sided log rank test at the 5% alpha level, Kaplan Meier curves, Cox regression analyses; difference in overall response rate was tested using a chi-squared test with Schouten correction. One interim analysis of efficacy and safety was planned, after approximately 250 of the calculated 445 deaths had been observed. This interim analysis provided the final analysis of PFS (with 505 events), after which the study was unblinded.
Summary (efficacy, safety, other results):
Efficacy: The addition of Avastin to IFN as first-line therapy for patients with metastatic clear cell renal cell carcinoma resulted in a clinically relevant and statistically significant increase in progression-free survival (median 10.2 vs. 5.4 months; hazard ratio 0.63, 95% CI [0.52,0.75], p<0.0001).
There was a strong trend towards an increase in overall survival (hazard ratio 0.79, 95% CI [0.62, 1.02], p=0.0670), and a statistically significant increase in time to disease progression (median 10.2 vs. 5.5 months; hazard ratio 0.61, 95% CI [0.51, 0.73], p<0.0001). There was a statistically significant increase in the percentage of responders in the Avastin + IFN arm (31%) compared to the placebo + IFN arm (13%) and a difference in response rates of 18.6, 95% CI [11.9, 25.2], p-value <0.0001. The duration of response and duration of stable disease were longer in the Avastin + IFN arm, 13.5 and 10.1 months, respectively, compared to placebo + IFN, 11.1 and 7.2 months, respectively. The benefit of the Avastin + IFN combination was observed in all Motzer risk categories of patients. Patients in the Avastin + IFN arm who reduced the dose of IFN according to the protocol had a 1 year PFS rate of 52%, compared to 43% in the total Avastin + IFN population.
Safety: The safety data were generally in line with observations in previous studies of Avastin in cancer patients. The overall incidence of severe and serious adverse events, and adverse events leading to withdrawals was 1.8-3.2-fold higher in the Avastin + IFN arm compared to the placebo + IFN arm. This was due in part to the adverse events known to occur with Avastin therapy, including bleeding, hypertension, proteinuria, thromboembolic events, and gastrointestinal perforations. The most common adverse events in both treatment arms were pyrexia (Avastin + IFN 45% vs. Pl + IFN 43%), anorexia (36% vs. 30%), fatigue (33% vs. 27%), asthenia (32% vs. 28%), and nausea (28% vs. 26%). All 5 are established IFN-associated toxicities, although anorexia and nausea may also be linked to the underlying disease. Some of the imbalance in the incidence of these types of AEs may be due to the longer median duration of IFN treatment in the Avastin + IFN arm (34 weeks vs. 20 weeks).
A total of 5 patients in the placebo + IFN arm and 7 in the Avastin + IFN arm died due to an adverse event during the time from first drug administration until 28 days after last study drug administration. An additional 2 patients in the placebo + IFN arm and one in the Avastin + IFN arm died due to an AE occurring later during follow-up. No particular pattern was seen in the types of events that resulted in death.
Laboratory tests did not show any new clinically relevant safety signals. The incidence of shifts from baseline was comparable between study arms with the exception of increases in proteinuria and GGT, which were more common in the Avastin + IFN arm, and a decrease in hemoglobin, which was more common in the placebo + IFN arm. The rate of other grade 3-4 laboratory abnormalities was comparable between study arms.
No notable changes in vital signs, ECG parameters, and Karnofsky performance status were observed during the study.
Conclusions:
This study demonstrated that the addition of Avastin to interferon alfa-2a therapy provides substantial benefit to patients with advanced and/or metastatic renal cell cancer. This was shown by a statistically significant, 1.9-fold increase in the median duration of progression-free survival (10.2 months versus 5.4 months), a longer time to disease progression, a longer time to treatment failure, and a >2-fold higher objective response rate. Although data for overall survival are immature, there was a strong trend for an increase of overall survival (hazard ratio 0.79, p-value 0.067) (and 0.75, p<0.0267 for stratified analysis).
The safety data were consistent with previous observations in cancer patients treated with Avastin . The pattern of the incidence of common adverse events included both the established side effects of IFN treatment (eg. asthenia and fatigue) as well as the known Avastin associated toxicities, such as bleeding/hemorrhage, hypertension, proteinuria, and thromboembolic events.
Click here for the protocol registry listing of this trial.
