Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE).

BACKGROUND: Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels. PATIENTS AND METHODS: CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate. RESULTS: A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, P = 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade ≥3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%). CONCLUSIONS: Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34.

Molecular imaging of tumor metabolism and apoptosis.

Increased metabolism in a number of cellular pathways is a common feature of malignant tumors. This metabolic hallmark of neoplastic tissue led to the development of radiopharmaceuticals for the assessment of transport and enzymatic activity for tumor diagnosis and staging. The malignant transformation causes the activation of oncogenic proteins and signaling pathways that stimulate glycolysis. The resulting high-glucose metabolism of cancer cells allows PET imaging using FDG. Other molecules frequently applied in preclinical and clinical studies are ¹¹C-methionine, tyrosine analogs and choline-based tracers. Using quantitative procedures they enable therapy monitoring by assessment of changes in transport and metabolization. As apoptosis is an important mechanism of cell death in tumors responding to treatment, non-invasive assessment of apoptosis using tracers for detection of phosphatidyl-serine presentation and/or caspase activation could be used as a surrogate marker for therapeutic efficacy.

[Iodide enrichment in malignant tumours after gene transfer]. / Gentechnisch modulierte Iodidanreicherung in malignen Tumoren.

After the cloning of the gene encoding the sodium-iodide symporter several trials were made to develop a radioiodine treatment for multiple tumour entities based on NIS gene transfer. These studies revealed in vitro as well as in vivo a tremendous enhancement of iodide accumulation, which was followed by a rapid efflux. Therapy effects were observed in vitro by clonogenic assays and in vivo by growth inhibition of the treated tumours. However, the interpretation of these results were largely different. Problems of radioiodine therapy after NIS transfer are low efficiency of gene transfer and the short exposure time for the tumours caused by the rapid efflux. Trials to enhance therapeutic efficiency by co-transfer of the gene encoding thyroperoxidase failed due to the low enzyme activity.