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
3252 - Genes involved in DNA replication, chromatin remodeling and cell cycle as potential biomarkers for therapy outcome to immune therapy in patients with metastatic cutaneous malignant melanoma
Presenter: Fernanda Costa Svedman
Session: Poster Display session 3
Resources:
Abstract
5545 - Phase Ib/II Study (SENSITIZE) assessing safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcome of domatinostat in combination with pembrolizumab in patients with advanced melanoma refractory/non-responding to prior checkpoint inhibitor therapy
Presenter: Jessica Hassel
Session: Poster Display session 3
Resources:
Abstract
5213 - Genomic landscape of primary malignant melanoma of esophagus
Presenter: Jie Dai
Session: Poster Display session 3
Resources:
Abstract
2716 - A phase III, randomised, double-blind study of adjuvant cemiplimab versus placebo post-surgery and radiation in patients with high-risk cutaneous squamous cell carcinoma (CSCC)
Presenter: Danny Rischin
Session: Poster Display session 3
Resources:
Abstract
3550 - ILLUMINATE 301: A randomized phase 3 study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy
Presenter: Marcus Butler
Session: Poster Display session 3
Resources:
Abstract
1645 - PRIME002 - Early phase II study of Azacitidine and Carboplatin priming for Avelumab in patients with advanced melanoma who are resistant to immunotherapy
Presenter: Andre Van Der Westhuizen
Session: Poster Display session 3
Resources:
Abstract
4440 - Pembrolizumab (pembro) Plus Lenvatinib (len) for First-Line Treatment of patients (pts) With Advanced Melanoma: Phase 3 LEAP-003 Study
Presenter: Alexander Eggermont
Session: Poster Display session 3
Resources:
Abstract
3454 - Proof of concept study with the histone deacetylase inhibitor vorinostat in patients with resistant BRAFV600 mutated advanced melanoma
Presenter: Sanne Huijberts
Session: Poster Display session 3
Resources:
Abstract
1832 - A phase Ia/Ib clinical study to evaluate the safety, pharmacokinetics (PK) and preliminary anti-tumor activity of FCN-159 in patients with advanced melanoma harboring NRAS-aberrant (Ia) and NRAS-mutation (Ib).
Presenter: Lu Si
Session: Poster Display session 3
Resources:
Abstract
3996 - A Phase I Clinical Trial Investigating the Therapeutic Cancer Vaccine UV1 in Combination with Pembrolizumab as First-Line Treatment of Patients with Malignant Melanoma
Presenter: Sanjiv Agarwala
Session: Poster Display session 3
Resources:
Abstract