Immune-targeted monoclonal antibodies blocking inhibitory immune checkpoints such as CTLA-4, PD-1 and PD-L1 have shown durable responses in multiple tumour types. These drugs generate a new type of complications in oncology: immune-related adverse events (ImAE). There is no established predictive biomarker to identify patients (pts) who are likely to develop severe ImAE. The hypothesis is that imAEs could result from host related pre-existing factors: Activation of self-reactive T and B cells, genetic predisposition, metabolic factors, enhanced cross reactivity between cancer cells, healthy cells and resident microbiota flora, and co-morbidity, concomitant treatments and patients’ environment. Response to immunotherapy could also be associated with pre-existing factors and tumor microenvironment features.
The study is a French ancillary study of a phase 3b, open-Label, multi-Centre, safety study of fixed-dose durvalumab + tremelimumab combination therapy or durvalumab monotherapy in advanced solid malignancies (STRONG) (NCT03084471). By collecting additional blood and tumour samples (table 1) the aim of this ancillary study is to define the immune phenotype, microbiome analysis of patients prior to an immunotherapy and who are subsequently developing an imAE or who achieve response to identify and characterize predictive factors of the toxicity and of efficacy. For both efficacy and safety objectives, respectively 85 and 300 patients will be required. The STRONG study currently includes pts with an urothelial and nonurothelial carcinoma of the urinary tract, treated with durvalumab as single agent at progression on or after of chemotherapy. As of July 2018, the IOPREDI ancillary study has been opened, 18 centres have been activated and 9 patients have been enrolled. Table 1 a) definition of AESI see section 6, b) only at baseline for polymorphisms, c) within 72 hours prior to the first treatment administration d) within 72 hours of occurrence of AESI.
Clinical trial identification
Legal entity responsible for the study
A. Marabelle, F. Ghiringhelli: Honoraria for scientific boards: AstraZeneca. M. Ayyoub, O. Adotevi, Y. Loriot, O. Lambotte: Honoraria for advisory boards: AstraZeneca. D. Cupissol, D. Damotte, N. Chaput: Honoraria for scientific committee meetings: AstraZeneca. J. Adam: Honoraria for advisory boards: AstraZeneca. B. Petre Lazar, M. Licour: Employee of AstraZeneca. All other authors have declared no conflicts of interest.Table: 30TiP
|Visit||Screening||Treatment period Baseline||Treatment period C2D1||Treatment period In case of AESIa ≥grade 2||Treatment period C3D1||At progression|
|Week||Weeks -4 to Week -1||Week 0||Week 4||Week 8|
|Autoantibodies Polymorphisms (serum)||Xb||X||X||X|
|Cytokines and soluble factors / Metabolic factors (plasma)||X||X||X|
|Immune cells RNA (whole blood)||X|
|Hb1Ac, glycaemia, T3 and T4||X||X||X|
|Stools sample||X c||X d|
|Telomerase, commensal and NYESO-1 T cells specific immune response (frozen PBMC)||X||X||X||X||X|
|Epithelial mesenchymal transition (tumor sample)||X|