Abstract 5294
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 1st and 2nd 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 1st and 2nd 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.
Resources from the same session
5694 - Findings from a new specialist remote Counselling Service for Neuroendocrine Neoplasm (NEN) patients and family members
Presenter: Catherine Bouvier
Session: Poster Display session 2
Resources:
Abstract
4725 - Hematologic malignancies in temozolomide-treated metastatic pancreatic neuroendocrine tumors
Presenter: Nicole Balmaceda
Session: Poster Display session 2
Resources:
Abstract
5842 - Efficacy and toxicity of combination chemotherapy with cyclophosphamide, vincristine and an anthracycline in patients with metastatic extrapulmonary neuroendocrine carcinoma
Presenter: Leonidas Apostolidis
Session: Poster Display session 2
Resources:
Abstract
1543 - An Australian multi-centre experience of the use of peptide receptor radionuclide therapy for bronchial carcinoid tumours.
Presenter: Lisi Lim
Session: Poster Display session 2
Resources:
Abstract
4175 - Extra-pulmonary (EP) high grade (HG) neuroendocrine carcinoma (NEC): real-life outcomes of fifty-eight patients from a Portuguese cancer center.
Presenter: Rita Conde
Session: Poster Display session 2
Resources:
Abstract
3274 - Efficacy of immune check-point inhibitors (ICPi) in large cell neuroendocrine tumors of lung (LCNET)
Presenter: Shira Sherman
Session: Poster Display session 2
Resources:
Abstract
3534 - HORMONET: Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression
Presenter: Milton Barros
Session: Poster Display session 2
Resources:
Abstract
2137 - Clinical utility of Metabolic Tumor Volume in Papillary Thyroid Carcinoma
Presenter: Norihiko Takemoto
Session: Poster Display session 2
Resources:
Abstract
3864 - Correlation of thyroglobulin (Tg) oscillations with progression-free survival (PFS) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid carcinoma (DTC) treated with multikinase inhibitors (MKI).
Presenter: Jorge Hernando Cubero
Session: Poster Display session 2
Resources:
Abstract
2820 - Analytical validation of a thyroid cancer diagnostic method based on the relative quantification of CLDN10, HMGA2 and LAMB3 expression
Presenter: Mateus Barrosfilho
Session: Poster Display session 2
Resources:
Abstract