Phase 3 Trial of BI 695502 Plus Chemotherapy Versus Bevacizumab Reference Product Plus Chemotherapy in Patients With Advanced Nonsquamous NSCLC.

INTRODUCTION: Biological therapies such as bevacizumab have improved survival in patients with NSCLC. This study was conducted to confirm the equivalent efficacy of the biosimilar candidate BI 695502 to the bevacizumab reference product (RP). METHODS: In this phase 3, multicenter, randomized, double-blind trial of adult patients with recurrent or metastatic NSCLC received up to 18 weeks of induction treatment with BI 695502 or bevacizumab RP 15 mg/kg plus paclitaxel and carboplatin. Subsequent maintenance therapy comprised BI 695502 or bevacizumab RP monotherapy until disease progression or unacceptable toxicity. The primary end point was the best overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 assessed by central imaging review, until 18 weeks after the start of treatment. RESULTS: In total, 671 patients were randomized at one-to-one ratio to BI 695502 or bevacizumab RP, of whom 335 and 328, respectively, received treatment. Of these, 228 (68.1%) and 256 (78.0%), respectively, proceeded to maintenance monotherapy. A manufacturing issue led to a small number of patients treated with BI 695502 switching to bevacizumab RP late in the study. The primary end point, best ORR, was 54.0% in the BI 695502 group and 63.1% in the bevacizumab RP group. The 90% confidence interval for the between-group ratio of best ORR (0.770 to 0.951) was within the prespecified range for equivalence (0.736-1.359). Adverse events were class-related and similar between the two treatment arms. CONCLUSIONS: This study revealed equivalent ORR after 18 weeks of treatment with BI 695502 or bevacizumab RP, with similar adverse event profiles.

A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects.

OBJECTIVES: This Phase I trial (INVICTAN®-1) evaluated three-way bioequivalence and safety of BI 695502 a bevacizumab biosimilar candidate, and reference product bevacizumab from two sources (US-approved Avastin®, Genentech; EU-approved Avastin, Roche). METHODS: Healthy male subjects (N = 91) were randomized 1:1:1 to receive a single intravenous infusion of 1 mg/kg of BI 695502 or US- or EU-approved Avastin. An interim analysis was planned when ~50% of subjects were evaluable for the primary end point to determine if the prespecified criteria for bioequivalence were achieved; if demonstrated, the study could be stopped early. The primary end point was area under the concentration-time curve (AUC) of the analyte in plasma from time zero extrapolated to infinity (AUC0-∞). Other pharmacokinetic (PK) parameters, safety, and in vitro binding affinity were also evaluated. RESULTS: The interim analysis demonstrated three-way bioequivalence for all comparisons. The confidence intervals around the geometric mean ratios of the primary and secondary PK parameters were within the predefined acceptance ranges. Study drugs were well tolerated with no clinically relevant differences in safety. CONCLUSION: BI 695502 and US- and EU-approved Avastin showed three-way bioequivalence with similar safety profile. CLINICAL TRIAL REGISTRATION: NCT01608087.

Concept for a study design in patients with severe community-acquired pneumonia: A randomised controlled trial with a novel IGM-enriched immunoglobulin preparation - The CIGMA study.

INTRODUCTION: Severe community-acquired pneumonia is defined as community-acquired pneumonia that requires intensive medical care. Mortality in these patients is still high depending on time and admission. Since bad outcomes may occur despite antibiotic therapy to treat severe community-acquired pneumonia, the focus has shifted to targeting the host response. The CIGMA Study examines the safety and efficacy of the novel IgM-enriched immunoglobulin preparation BT086 when added to standard of care treatment. METHODS/DESIGN: The aim of this multicentre, randomised, placebo-controlled, double-blind, parallel-group, adaptive group-sequential phase II study is to determine the efficacy and safety of BT086, an IgM-enriched immunoglobulin preparation, as an adjunctive treatment in mechanically-ventilated patients with severe community-acquired pneumonia. The increase of ventilator-free days is the primary endpoint in this study. For this trial, ventilator-free days are defined as the number of days between successful extubation from endotracheal ventilation and day 28 after enrolment of the patient into the study. Two interim analyses were considered for this study. DISCUSSION: Several novel agents for treatment of sepsis have been evaluated in the last two decades; however, none has significantly reduced mortality rates. Failure was attributed to the heterogeneity of septic patients or sepsis. Severe community-acquired pneumonia was chosen as the indication for this study to increase homogeneity within this patient population. TRIAL REGISTRATION: EUDRACT 2010-022380-35.

The French polidocanol study on long-term side effects: a survey covering 3,357 patient years.

BACKGROUND: AIMS Short- and mid-term side effects of sclerotherapy, in particular with polidocanol (lauromacrogol 400), have been previously described in our registry of 12,173 sessions. The objective of this follow-up registry was to evaluate the long-term incidence of adverse events with polidocanol. METHODS: The physicians involved in the initial French registry were contacted and asked to partake in the follow-up survey. Initially included patients were controlled at the latest possible date to determine whether a complication had occurred after the end of the initial survey. RESULTS: Data on 1,605 patients included in the French registry were reviewed with a maximum follow-up of 60 months, covering 3,357 patient years. Five (0.4%) adverse events were observed in patients treated with liquid polidocanol and 46 (1.1%) in patients treated with polidocanol foam. The most frequent side effects were visual disturbances (n=14), and the most severe were muscular vein thrombosis (n=8). The onset of side effects was mostly observed directly after sclerotherapy or in the 6 months after (84% in the first year). One deep vein thrombosis recurrence occurred in a patient with heterozygote Factor V Leiden after stopping anticoagulant treatment (foam sclerotherapy). CONCLUSIONS: Foam sclerotherapy is a recognized reference method in the treatment of varicose veins of all types. This study demonstrates that polidocanol is a safe sclerosing agent in the short and long term.