INFORM2 NivEnt: The first trial of the INFORM2 biomarker driven phase I/II trial series: the combination of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies

Cornelis M van Tilburg, Ruth Witt, Melanie Heiss, Kristian W Pajtler, Christoph Plass, Isabel Poschke, Michael Platten, Inga Harting, Oliver Sedlaczek, Angelika Freitag, David Meyrath, Lenka Taylor, Gnana Prakash Balasubramanian, Natalie Jäger, Elke Pfaff, Barbara C Jones, Till Milde, Stefan M Pfister, David T W Jones, Annette Kopp-Schneider, Olaf Witt, Cornelis M van Tilburg, Ruth Witt, Melanie Heiss, Kristian W Pajtler, Christoph Plass, Isabel Poschke, Michael Platten, Inga Harting, Oliver Sedlaczek, Angelika Freitag, David Meyrath, Lenka Taylor, Gnana Prakash Balasubramanian, Natalie Jäger, Elke Pfaff, Barbara C Jones, Till Milde, Stefan M Pfister, David T W Jones, Annette Kopp-Schneider, Olaf Witt

Abstract

Background: Pediatric patients with relapsed or refractory disease represent a population with a desperate medical need. The aim of the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) program is to translate next generation molecular diagnostics into a biomarker driven treatment strategy. The program consists of two major foundations: the INFORM registry providing a molecular screening platform and the INFORM2 series of biomarker driven phase I/II trials. The INFORM2 NivEnt trial aims to determine the recommended phase 2 dose (RP2D) of the combination treatment of nivolumab and entinostat (phase I) and to evaluate activity and safety (phase II).

Methods: This is an exploratory non-randomized, open-label, multinational and multicenter seamless phase I/II trial in children and adolescents with relapsed / refractory or progressive high-risk solid tumors and CNS tumors. The phase I is divided in 2 age cohorts: 12-21 years and 6-11 years and follows a 3 + 3 design with two dose levels for entinostat (2 mg/m2 and 4 mg/m2 once per week) and fixed dose nivolumab (3 mg/kg every 2 weeks). Patients entering the trial on RP2D 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). A Bayesian adaptive design will be used to early stop cohorts that fail to show evidence of activity. The maximum number of patients is 128.

Discussion: This trial intends to exploit the immune enhancing effects of entinostat on nivolumab using an innovative biomarker driven approach in order to maximize the chance of detecting signs of activity. It prevents exposure to unnecessary risks by applying the Bayesian adaptive design for early stopping for futility. The adaptive biomarker driven design provides an innovative approach accelerating drug development and reducing exposure to investigational treatments in these vulnerable children at the same time.

Trial registration: ClinicalTrials.gov, NCT03838042. Registered on 12 February 2019.

Keywords: Bayesian design; Biomarker; Checkpoint inhibition; Child; Entinostat; HDAC; Nivolumab; Phase I/II.

Conflict of interest statement

C.v.T. reports personal fees from Novartis and personal fees from Bayer, outside the submitted work. M.P. reports non-financial support from Pfizer, non-financial support from Merck, non-financial support from Bayer, personal fees from Bayer, personal fees from Apogenix and personal fees from Affiris, outside the submitted work. In addition, M.P. has a patent “Treatment of Kynurenin-producing Tumors with AhR Antagonists” with royalties paid to Bayer, and a patent “Means and methods for treating and/or preventing natural Ahr ligand-dependent cancer” with royalties paid to Bayer. O.W. reports personal fees from Novartis and personal fees from Astra Zeneca, outside the submitted work. The other coauthors have nothing to declare.

Figures

Fig. 1
Fig. 1
Schematic study overview. Figure shows the workflow of the INFORM Registry molecular pipeline followed by the respective phase I and phase II of the INFORM2 NivEnt trial. WES, whole exome sequencing; LC-WGS, low coverage whole genome sequencing; RNA-Seq, RNA sequencing. a Or equivalently valid molecular pipelines
Fig. 2
Fig. 2
Decision boundaries for futility and efficacy in terms of number of observed responders among enrolled patients. The same criteria apply for interim and final analyses

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