Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer.

PURPOSE: R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study. PATIENTS AND METHODS: Patients with advanced-stage non–small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate. RESULTS: In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo. CONCLUSION: The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR

Thalidomide in the treatment of erythema nodosum leprosum (ENL): systematic review of clinical trials and prospects of new investigations

FUNDAMENTOS: A hanseníase persiste como problema de saúde pública, e episódios de ENH são eventos agudos que ocorrem antes, durante e após PQT. Na última década, o uso da talidomida como agente imunomodulador foi expandido a outras doenças. OBJETIVOS: realizar revisão sistemática dos ensaios clínicos publicados sobre a eficácia e efeitos colaterais da talidomida no ENH. Descrever metodologia e resultados da triagem para recrutamento de ensaio clínico visando avaliar dose-resposta da talidomida seguida de desmame no ENH moderado e grave, realizado no Brasil. MÉTODOS: Analisaram-se ensaios publicados sobre talidomida no ENH. Foi delineado um ensaio clínico duplo-cego randomizado para avaliar dose de 100 thalid 300mg/dia de talidomida durante fase aguda de ENH, seguida de desmame da talidomida, thalid placebo. Para este ensaio clínico descreve-se metodologia e dados de recrutamento de pacientes, com ênfase na gravidade dos episódios de ENH. RESULTADOS: Os seis ensaios clínicos publicados nas décadas de 1960 e 1970 apontam para o benefício da talidomida no ENH, embora diferenças metodológicas dificultem a comparação. Na fase de recrutamento do ensaio brasileiro, dos 143 pacientes de ENH triados, 65% eram potencialmente elegíveis. A associação com neurite em 56,4% dos ENH moderados e graves exigiu co-intervenção com corticosteróide. CONCLUSÃO: O padrão de recrutamento dos pacientes evidenciou alta freqüência de neurite nos episódios de ENH. O esquema de talidomida isolada no ENH foi avaliado como infreqüente na prática clínica brasileira. O desafio atual é acumular evidências sobre a eficácia e efeitos colaterais da talidomida em associação com corticosteróides.BACKGROUND: Leprosy remains a public health problem. Episodes of erythema nodosum leprosum (ENL) are acute events that occur before, during and after polychemotherapy. In the last decade, the use of thalidomide as an immunomodulating agent was expanded to other diseases. OBJECTIVES: To perform a systematic review of published clinical trials on efficacy and side effects of thalidomide in ENL. To describe the methodology and screening results of recruiting for a clinical trial performed in Brazil, which aimed to assess the dose-response of thalidomide followed by tapering regimen in severe and moderate cases of ENL. METHODS: Published clinical trials on the use of thalidomide in ENL were analyzed. A randomized, double-blind clinical trial was designed to evaluate the doses of 100mg versus 300mg/day thalidomide during the acute stage of ENL, followed by thalidomide tapering regimen versus placebo. For this clinical trial, the methodology and data for enrollment of patients were described, with an emphasis on severity of ENL episodes. RESULTS: Six clinical trials published in the 1960's and 1970's indicated the benefits of thalidomide in ENL, although methodological differences made comparison difficult. In the enrollment stage of the Brazilian trial, 65% of patients were potentially eligible out of 143 ENL patients screened. The association with neuritis in 56.4% of moderate and severe cases of ENL required the co-intervention with steroids. CONCLUSION: The patients' enrollment pattern demonstrated high frequency of neuritis in ENL episodes. The treatment regimen with thalidomide in monotherapy for ENL was considered infrequent in the clinical practice in Brazil. The current challenge is to accumulate evidence about efficacy and side effects of thalidomide in combination with steroids