5294 - EMERGE: Epigenetic Modulation of the Immune Response in Gastrointestinal cancers

Background

Checkpoint inhibitors (CPIs) have transformed treatment of many malignancies. However, to date, response to checkpoint blockade in unselected gastrointestinal (GI) cancers has been disappointing. Tumours which display a non-T-cell inflamed phenotype such as mismatch repair proficient (MMRp) oesophagogastric (OG) and colorectal cancers (CRC) respond less frequently to CPIs. Changes in tumour expression of antigens and increased immune infiltrate are associated with improved response to CPIs. Epigenetic modulation of tumours using HDAC inhibitors can lead to increased tumour antigen presentation, immune cell infiltrates and thereby may increase the chance of response to immunotherapy.

Trial design

EMERGE is designed to evaluate the safety and efficacy of domatinostat, a selective class 1 histone deacetylase inhibitor in combination with avelumab, an anti-PD-L1 monoclonal antibody in patients with previously treated, inoperable or metastatic MMRp OG and CRC. The trial is conducted in 2 stages: Phase IIA will establish a safe and tolerated dose of domatinostat plus avelumab using a 3 + 3 dose finding design and escalating doses of domatinostat will be examined, dosing of avelumab will remain constant. The phase IIB will use a Simon two stage optimal design to assess efficacy of the combination in achieving radiological response according to RECIST v1.1. The primary endpoint of the phase IIB is best objective response rate (ORR) at 6 months. To rule out an ORR of 5% in the CRC cohort, while aiming for 20%, 1/10 and 4/29 responses are required in the 1^st and 2^nd stages respectively. To rule out an ORR of 15% in the OG cohort while aiming for 35%, 2/9 and 9/34 responses are required in the 1^st and 2^nd stages respectively with a 1-sided alpha of 5% and 80% power. Secondary endpoints are DoOR, PFS, OS, DCR, safety and tolerability. Exploratory objectives will investigate dynamic changes in expression of tumour associated antigens and immune infiltrates in baseline and on-treatment biopsies and correlate baseline tumour characteristics and circulating biomarkers with tumour response and survival. Recruitment commenced in January 2019, 83 patients will be recruited over 3 years. (ClinTrials.gov. ID: NCT03812796).

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Royal Marsden Hospital NHS Foundation Trust.

Funding

Royal Marsden Hospital NHS Foundation Trust, 4SC.

Disclosure

M. Hubank: Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (self), Research grant / Funding (institution): Roche Diagnostics; Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (self), Research grant / Funding (institution): Guardant Health; Research grant / Funding (self), Research grant / Funding (institution): Celgene; Research grant / Funding (self), Research grant / Funding (institution): Eli Lilley. I. Chau: Honoraria (self): Eli-Lilly; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Bristol Meyers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Servier; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. D. Cunningham: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck. All other authors have declared no conflicts of interest.