LAUSR

Abstract Background Preliminary studies have suggested that the activity of anti-PD-1 immune check-point inhibitors in thyroid cancer is low. However, we hypothesize that combining CTLA-4 and PD-L1 clockade could have a higher effet in the setting of refractory thyroid carcinomas, in which the process of de-differentiation and evasive tumor resistance are associated with increased mutational load. Trial design This prospective, multi-center, open-label, phase II study will evaluate the efficacy and safety of Durvalumab plus Tremelimumab within three parallel cohorts: differentiated (DTC), medullary (MTC), and anaplastic (ATC) thyroid cancers. Pts will receive Durvalumab 1500mg plus Tremelimumab 75mg every 4 weeks for up to 4 cycles followed by Durvalumab until PD, unacceptable toxicity or patients’ decision. Main end point in cohorts 1 and 2 is progression-free survival (PFS). We hypothesize an increase of 6-months from 25% in historical cohorts up to 45%. A Simon two-stage design will be employed with 17 pts per cohort in the first phase. If 5/17 pts in each cohort (DTC and MTC) are event free and without unacceptable toxicity at 6 months in the first stage, 19 additional pts will be reruited up to 36 pts per cohort. For cohort 3 (ATC), we hypothesize an improvement the probability of being alive at 6 months from 5% in historical cohorts up to 35%. 12 pts are needed in this cohort. Secondary objectives include overall response rate by irRECIST and RECIST, duration of response, safety profile and biomarkers. The main inclusion criteria for the three cohorts are: Cohort 1: Pts with locally advanced or metastatic DTC after PD on multikinase inhibitors (MKIs). Cohort 2: Pts with locally advanced or metastatic MTC after PD to MKIs. Cohort 3: Pts with ATC irrespective of prior therapy. No prior treatment with immune checkpoint inhibitors is allowed. The study is currently recruiting pts with 6 out of 46 planned pts enrolled at time of submission. Clinical trial identification EudraCT: 2018-001066-42. Legal entity responsible for the study The authors. Funding Spanish Group of Neuroendocrine and Endocrine Tumors (GETNE). Disclosure J. Hernando Cubero: Speaker Bureau / Expert testimony: Eisai, Ipsen, Roche, Angelini; Travel / Accommodation / Expenses: Ipsen, Novartis, AAA, Roche, AstraZeneca, Eisai. M. Taberna Sanz: Advisory / Consultancy: Merck, Nanobiotics, AstraZeneca, MSD and Bristol Myers..A. Carmona Bayonas: Speaker Bureau / Expert testimony: Novartis, Ipsen; Travel / Accommodation / Expenses: Novartis, Ipsen. L. Iglesias: Advisory / Consultancy: Merck Serono, MSD, BMS, Bayer and Sanofi; Speaker Bureau / Expert testimony: Merck Serono, MSD, AstraZeneca and BMS..E. Grande: Advisory / Consultancy: Pfizer, Ipsen, BMS, Eisai, Roche, MSD, Sanofi, Adacap, Novartis, EUSA Pharma, Pierre Fabre, Lexicon, Celgene; Research grant / Funding (institution): MSD, Roche. J.M. Trigo Perez: Advisory / Consultancy: BMS, MSD, Behringer, GSK; Speaker Bureau / Expert testimony: AstraZeneca, Bayer, Roche; Travel / Accommodation / Expenses: MSD, BMS. T. Alonso Gordoa: Advisory / Consultancy: BMS, MSD, Roche, Astellas, IPSEN, Sanofi; Speaker Bureau / Expert testimony: Pfizer, Ipsen, Janssen, Astellas, Novartis.; Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Pfizer, Sanofi. J. Lavernia: Speaker Bureau / Expert testimony: Roche, BMS, Sun Pharma, Sanofi and Merck Serono. J. Capdevila: Advisory / Consultancy: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, AAA, Amgen, Sanofi, Merck; Honoraria (institution): Eisai, Novartis, Ipsen, AstraZeneca, Pfizer, AAA. All other authors have declared no conflicts of interest.