eprintid: 10152373 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/15/23/73 datestamp: 2022-07-20 14:55:45 lastmod: 2022-07-20 14:55:45 status_changed: 2022-07-20 14:55:45 type: article metadata_visibility: show sword_depositor: 699 creators_name: Papadatos-Pastos, D creators_name: Yuan, W creators_name: Pal, A creators_name: Crespo, M creators_name: Ferreira, A creators_name: Gurel, B creators_name: Prout, T creators_name: Ameratunga, M creators_name: Chénard-Poirier, M creators_name: Curcean, A creators_name: Bertan, C creators_name: Baker, C creators_name: Miranda, S creators_name: Masrour, N creators_name: Chen, W creators_name: Pereira, R creators_name: Figueiredo, I creators_name: Morilla, R creators_name: Jenkins, B creators_name: Zachariou, A creators_name: Riisnaes, R creators_name: Parmar, M creators_name: Turner, A creators_name: Carreira, S creators_name: Yap, C creators_name: Brown, R creators_name: Tunariu, N creators_name: Banerji, U creators_name: Lopez, J creators_name: De Bono, J creators_name: Minchom, A title: Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors ispublished: pub divisions: UCL divisions: J38 divisions: D65 divisions: B02 keywords: drug therapy, combination, guadecitabine, methylation, pembrolizumab, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Humans, Immune Checkpoint Inhibitors, Neoplasms note: http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/. abstract: Background: Data suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial (NCT02998567) of guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance. Methods: Patients received guadecitabine (45 mg/m 2 or 30 mg/m 2, administered subcutaneously on days 1-4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies. Results: Between January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m 2, days 1-4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m 2 with none reported at guadecitabine 30 mg/m 2. The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE-1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5' untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses. Conclusions: Guadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated. date: 2022-06-18 date_type: published publisher: BMJ official_url: http://dx.doi.org/10.1136/jitc-2022-004495 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1963186 doi: 10.1136/jitc-2022-004495 medium: Print pii: jitc-2022-004495 lyricists_name: Parmar, Mahesh lyricists_id: MKBPA56 actors_name: Kalinowski, Damian actors_id: DKALI47 actors_role: owner funding_acknowledgements: [Astex Pharmaceuticals]; [Merck]; [National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research and Imperial College]; [Cancer Centre grant from Cancer Research U]; [Experimental Cancer Medicine Centre (ECMC) Initiative to The Institute of Cancer Research and Royal Marsden] full_text_status: public publication: Journal for ImmunoTherapy of Cancer volume: 10 number: 6 article_number: e004495 event_location: England citation: Papadatos-Pastos, D; Yuan, W; Pal, A; Crespo, M; Ferreira, A; Gurel, B; Prout, T; ... Minchom, A; + view all <#> Papadatos-Pastos, D; Yuan, W; Pal, A; Crespo, M; Ferreira, A; Gurel, B; Prout, T; Ameratunga, M; Chénard-Poirier, M; Curcean, A; Bertan, C; Baker, C; Miranda, S; Masrour, N; Chen, W; Pereira, R; Figueiredo, I; Morilla, R; Jenkins, B; Zachariou, A; Riisnaes, R; Parmar, M; Turner, A; Carreira, S; Yap, C; Brown, R; Tunariu, N; Banerji, U; Lopez, J; De Bono, J; Minchom, A; - view fewer <#> (2022) Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors. Journal for ImmunoTherapy of Cancer , 10 (6) , Article e004495. 10.1136/jitc-2022-004495 <https://doi.org/10.1136/jitc-2022-004495>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10152373/1/Parmar_Phase%201%20dose-escalation%20study%20of%20guadecitabine_VoR.pdf