Abstract 4779
Background
Despite the application of PD-1 inhibitors in clinical practice in SCCHN, only a fraction of patients shows durable responses to monotherapy. Numerous combinatorial strategies have been utilized to attempt to augment immunotherapy efficacy. While dysregulated tumour metabolism (TM) is a critical feature of the tumour microenvironment (TME) and impacts immune function within the TME, much remains to be done to bridge these areas and explore therapeutic opportunities. Recent murine xenograft and clinical translational data suggests that metformin alters TM, and preclinical data suggests possible potentiation of PD-1 axis inhibition by metformin.
Methods
This is a single-center, randomized trial for patients with all stages of resectable SCCHN, with planned enrollment of 38 patients. Part 1, which has been completed, was a safety run-in with 6 patients treated with metformin (met) + durvalumab (durva) for safety evaluation. Part 2 will enroll 32 additional patients with a 3:1 randomization to treatment arm A (met 1000 mg BID Day 1-31 + durva 1500 mg IV x 1 on Day 3) and treatment arm B (durva 1500 mg IV x 1). Tumor and blood will be collected pre and post treatment with analysis of immune cell composition. The primary endpoint is the combined effect of metformin and durvalumab on the immune TME, specifically with respect to alterations in T cell and macrophage polarization. Secondary endpoints include safety and tolerability, alterations in immunohistochemical markers of the TME, transcriptome and circulating DNA analysis, and objective response rate.
Results
Six patients were enrolled in Part 1. All were males with a mean age of 65.7 ± 6.8 years. All patients had grade 1 adverse events (AE) consisting mainly of gastrointestinal (diarrhea, nausea, or abdominal cramps) and constitutional (anorexia, fatigue, or sleep disturbance) symptoms. No patient experienced AE > = grade 2. All patients were able to proceed to surgery without unanticipated delays.
Conclusions
The combination of met and durva was safe in the first cohort of patients. Enrollment for Part 2 is ongoing.
Clinical trial identification
NCT03618654.
Editorial acknowledgement
Legal entity responsible for the study
Sidney Kimmel Cancer Center at Thomas Jefferson University Sidney Kimmel Cancer Center at Thomas Jefferson University Sidney Kimmel Cancer Center at Thomas Jefferson University Sidney Kimmel Cancer Center at Thomas Jefferson University.
Funding
Sidney Kimmel Cancer Center at Thomas Jefferson University.
Disclosure
J.M. Johnson: Research grant / Funding (self): Bristol-Myers Squibb. A. Argiris: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: Debiopharm Group; Advisory / Consultancy: Aspyrian Therapeutics; Research grant / Funding (self): Genentech/Roche. A. Luginbuhl: Research grant / Funding (self): Bristol-Myers Squibb. R. Zinner: Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, An Immediate Family Member: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Lilly. U. Rodeck: Shareholder / Stockholder / Stock options: Akriveia Therapeutics; Research grant / Funding (self): Advaxis; Licensing / Royalties: Several Patents. J.M. Curry: Research grant / Funding (self): AstraZeneca. All other authors have declared no conflicts of interest.
Resources from the same session
2316 - A 3D co-culture platform of breast cancer and patient derived immune cells to analyse the response to chemotherapy and immunotherapies
Presenter: Diana Saraiva
Session: Poster Display session 3
Resources:
Abstract
4290 - Characterization of the mechanism of action and efficacy of MEN1611 (PA799), a novel PI3K inhibitor, in breast cancer preclinical models.
Presenter: Alessio Fiascarelli
Session: Poster Display session 3
Resources:
Abstract
2167 - Neat-1: culprit lnRNA tying PIG-C, MSLN, CD80 in TNBC
Presenter: Nada Hussein
Session: Poster Display session 3
Resources:
Abstract
1829 - A novel RAF/MEK inhibitor CH5126766 in phase 1 clinical trial has an effectiveness in the combination with eribulin for the treatment of triple negative breast cancer
Presenter: Hisako Ono
Session: Poster Display session 3
Resources:
Abstract
4357 - Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer
Presenter: Eva Galan-Moya
Session: Poster Display session 3
Resources:
Abstract
5163 - Preclinical Evaluation targeting both IGF1R and IR in Triple Negative Breast Cancer
Presenter: Alex Eustace
Session: Poster Display session 3
Resources:
Abstract
832 - Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo.
Presenter: Jia-Hong Chen
Session: Poster Display session 3
Resources:
Abstract
3781 - Pharmacological screening with Chk1 inhibitors identify synergistic agents to overcome resistance to platinums in basal breast and ovarian cancer
Presenter: Ana Lucia Sanabria
Session: Poster Display session 3
Resources:
Abstract
3275 - Comparison of 11 circulating miRNAs and CA125 kinetics in ovarian cancer during first line treatment: data from the randomized CHIVA trial (a GINECO-GCIG study)
Presenter: Patrick Robelin
Session: Poster Display session 3
Resources:
Abstract
3391 - Inhibiting Ehmt2 and Ezh2 histone methyltransferases alters the immune microenvironment in a Trp53-/- murine ovarian cancer model
Presenter: Pavlina Spiliopoulou
Session: Poster Display session 3
Resources:
Abstract