Phase I results of the INFORM2 combination study of nivolumab and entinostat in children and adolescents: INFORM2 NivEnt.
Authors: van Tilburg Cornelis Martinus , Heiss Melanie , Øra Ingrid , Beilken Andreas , Dirksen Uta , Gottardo Nicholas G. , Khuong-Quang Dong-Anh , Hansford Jordan , Hutter Caroline , Van der Lugt Jasper , Thorwarth Anne , Poschke Isabel , Harting Inga , Sedlaczek Oliver , Beck Pengbo , Freitag Angelika , Jones David T.W. , Jäger Natalie , Kopp-Schneider Annette , Witt Olaf 
Published: June 2022

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Background: Pediatric patients with relapsed or refractory high-risk solid and CNS tumors have dismal survival. To date treatment with immune checkpoint inhibitors in this population has been disappointing. This study exploits the immune enhancing effects of entinostat on nivolumab in biomarker enriched subpopulations. The study aims to determine the pediatric recommended phase II dose (pRP2D) and to evaluate activity and safety. Methods: This is an exploratory non-randomized, open-label, multinational seamless phase I/II trial in children and adolescents with relapsed / refractory or progressive high-risk solid and CNS tumors. The phase I is divided in 2 age cohorts: 12–21 years (y) and 6–11y and follows a 3 + 3 design with two dose levels for entinostat (dose level 1: 2 mg/m2 and dose level 2: 4 mg/m2 once per week) and fixed dose nivolumab (3 mg/kg every 2 weeks). Patients entering the trial on pRP2D can seamlessly enter phase II which consists of a biomarker defined four group basket trial: high mutational load (group A), high PD-L1 mRNA expression (group B), focal MYC(N) amplification (group C), low mutational load and low PD-L1 mRNA expression and no MYC(N) amplification (group D). Results: The first patient was enrolled in May 2020 and at the time of the data cut (21-JAN-2022), 19 patients were treated. The median age at enrollment was 14 y. In the 12 – 21y cohort 15 patients were enrolled and four patients in the 6 – 11y cohort. The most frequent treatment-related AEs to date were thrombocytopenia in six (32%), nausea and vomiting both in four (21%), and neutropenia in three patients (16%). Five patients (26%) experienced grade 3/4 mostly reversible treatment-related AEs, e.g. neutropenia/leukopenia. No treatment related deaths were reported. In the 6 – 11y cohort dose escalation is ongoing. In the 12 – 21y cohort, one DLT (CTCAE grade 3 thrombocytopenia) was observed in six patients on dose level two, which was determined as the pRP2D of the combination. At the time of the data cut, 10 patients (six in arm D and four patients in which the biomarker group was not yet determined) had received at least one RECIST/RANO response evaluation by central review in phase II. One patient (17%) in arm D with metastatic relapsed renal cell carcinoma (RCC) harboring a typical PRCC-TFE3 fusion showed a PR after two cycles and finally achieved an ongoing CR. Extensive explorative analyses of immune signatures derived from INFORM RNA-Seq and WES data revealed that both the primary diagnosis and the current relapse samples harbored a remarkable high immune cell infiltration, especially CD8+ T-cells. Conclusions: The first and ongoing global INFORM2 trial has identified the pRP2D for the nivolumab and entinostat combination in the older age cohort with good tolerability. A patient with metastasized relapsed RCC experienced a CR. The role of immune infiltration as a potential predictive biomarker is currently being explored. Clinical trial information: NCT03838042.