Abstract CT270: A randomized, multi-center, phase II study of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab in melanoma and NSCLC patients resistant to anti-PD-1/-PD-L1: The NIBIT-ML1 Study
Authors: Di Giacomo Anna Maria , Calabrò Luana , Danielli Riccardo , Valente Monica , Gambale Elisabetta , Coral Sandra , Amato Giovanni , Keer Harold , Giannarelli Diana , Azab Mohammad , Anichini Andrea , Covre Alessia , Maio Michele 
Published: September 2020

Abstract
Background: Therapeutic targeting of the PD-1/PDL-1 axis significantly increases the survival of melanoma (MM) and non-small cell lung cancer (NSCLC) patients. Despite this unprecedented efficacy, a sizeable proportion of MM and NSCLC patients fails to benefit from therapy due to primary or secondary resistance to treatment. In this scenario, deepening the knowledge on mechanism(s) underlying treatment failure allows to design novel, mechanism-based, therapeutic approaches to overcome resistance to anti-PD-1/PDL-1 therapy. Along this line, we have extensively characterized the immunomodulatory properties of DNA hypomethylating agents (DHA) in different human malignances. Exposure of neoplastic cells to DHA efficiently improved antigen-restricted and -unrestricted T cell recognition of cancer cells in vitro through the upregulation/induction of the expression of epigenetically regulated tumor associated antigens, HLA class I and/or accessory/co-stimulatory molecules by neoplastic cells. Supporting these ex vivo data, combining the systemic administration of DHA (ie, decitabine or guadecitabine) with antibodies to different immune checkpoints significantly reduced tumor growth of murine syngeneic grafts, compared to single-agent therapy. Supporting these pre-clinical findings, our phase Ib NIBIT-M4 study has been the first clinical trial demonstrating that systemic administration of guadecitabine followed by CTLA-4 blockade with ipilimumab is safe and tolerable in MM patients, shows a promising anti-tumor, and induces a significant modulation of immune related pathways in tumor samples (Di Giacomo AM, Clin Cancer Res 2019). Prompted by these results and to further explore the efficacy of DHA combined with immune-checkpoints blockade we have designed and activated the NIBIT-ML1 trial. This study aims at investigating the efficacy of guadecitabine combined with ipilimumab and nivolumab in reverting the resistance to PD-1/PDL-1 therapy of MM and NSCLC patients. Methods: The NIBIT-ML1 is a randomized, phase II study designed according to the two stages optimal design by Simon, in unresectable Stage III or Stage IV MM (Cohort A) or NSCLC (Cohort B) patients who failed therapy with anti-PD-1/PDL-1 as last treatment. Primary objective of the study is immune (i)-ORR according to iRECIST criteria. Secondary objectives include safety, DCR, PFS, median OS, and survival rate at 1 and 2-years. Extensive cellular and molecular immune correlates will also be explored. Following a safety run-in phase in 6 subjects per Cohort, eligible patients will be randomized to receive: guadecitabine plus ipilimumab and nivolumab (ARM A) or ipilimumab and nivolumab (ARM B). Sample size will range from 6 to 92 patients per Cohort. The first patient first visit is foreseen by March 2020 (NCT04250246)
Citation Format: Anna Maria Di Giacomo, Luana Calabrò, Riccardo Danielli, Monica Valente, Elisabetta Gambale, Sandra Coral, Giovanni Amato, Harold Keer, Diana Giannarelli, Mohammad Azab, Andrea Anichini, Alessia Covre, Michele Maio. A randomized, multi-center, phase II study of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab in melanoma and NSCLC patients resistant to anti-PD-1/-PD-L1: The NIBIT-ML1 Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT270.