A phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumours (NCT03447314)

Abstract

Background Toll-like receptor (TLR) activation can enhance a range of antitumor immune responses via production of inflammatory cytokines and modulation of immune cells in the tumor microenvironment. GSK1795091 is a synthetic TLR4 agonist that showed immunomodulatory activity in preclinical cancer models (Gao et al. J Clin Oncol 2018) and successfully completed a safety, pharmacokinetic (PK) and pharmacodynamic (PD) study using IV administration in healthy volunteers. The current study will evaluate GSK1795091 with immunotherapies that have highly complementary mechanisms of action and supporting preclinical data (e.g. GSK3174998 [an OX40 agonist], GSK3359609 [an ICOS agonist], or pembrolizumab [a PD-1 inhibitor]) with the aim of generating greater antitumor activity than with monotherapy. Trial design This is a Phase I, open-label, non-randomized study in patients (≥18 years) with advanced solid tumors who have progressed on, or are ineligible for, standard therapy. In Part 1, up to 72 patients will be divided into 3 arms: GSK1795091 (50–250ng IV; dose escalation) plus either GSK3174998 (24mg IV), GSK3359609 (80mg IV), or pembrolizumab (200mg IV). GSK1795091 will be given weekly for 12 weeks; combination partners will be administered every 3 weeks (q3w) from Week 3 to allow a 2-week GSK1795091 monotherapy run-in period. After Week 12, GSK1795091 will be administered q3w, coinciding with the combination partner. Up to 6 participants per dose level may be enrolled into a PK/PD cohort for each combination. In Part 2, initial expansion cohorts of up to 15 patients with head and neck squamous cell carcinoma will be enrolled in each treatment arm at the dose(s) identified in Part 1. The primary objective is to evaluate the safety and tolerability of GSK1795091 combination therapy. Additional objectives include clinical activity, PK, PD and immunogenicity. Enrollment for the GSK1795091 + GSK3174998 arm began in March 2018; 12 patients have completed the first 2 dose cohorts. The remaining arms will commence enrollment in 1Q2019. Funded by GlaxoSmithKline. Clinical trial identification NCT03447314. Editorial acknowledgement Medical writing and editorial assistance was provided by Leigh O’Connor-Jones, PhD, of Fishawack Indicia Ltd and was funded by GSK. Legal entity responsible for the study GlaxoSmithKline. Funding GlaxoSmithKline. Disclosure A.R. Hansen: Advisory / Consultancy: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Research grant / Funding (institution): Karyopharm Therapeutics. J. Strauss: Shareholder / Stockholder / Stock options: Abbvie; Shareholder / Stockholder / Stock options: Abbott Laboratories; Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Shareholder / Stockholder / Stock options: Intuitive Surgical; Shareholder / Stockholder / Stock options: Johnson and Johnson; Shareholder / Stockholder / Stock options: Merck; Advisory / Consultancy, Consulting agreement in 2017, no longer active: Tempus; Advisory / Consultancy, Member of advisory board: Dialectic Therapeutics. J. Chaves: Research grant / Funding (self), Research grant / Funding (institution): Immune Design; Research grant / Funding (self), Research grant / Funding (institution): Zymeworks; Research grant / Funding (self), Research grant / Funding (institution): Calithera; Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (self), Research grant / Funding (institution): Merck; Research grant / Funding (self), Research grant / Funding (institution): EMD Serono; Research grant / Funding (self), Research grant / Funding (institution): Novartis; Research grant / Funding (self), Research grant / Funding (institution): Roche; Research grant / Funding (self), Research grant / Funding (institution): Genentech; Research grant / Funding (self), Research grant / Funding (institution): Array BioPharma; Research grant / Funding (self), Research grant / Funding (institution): Incyte; Research grant / Funding (self), Research grant / Funding (institution): Nektar; Research grant / Funding (self), Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (self), Research grant / Funding (institution): Regeneron; Research grant / Funding (self), Research grant / Funding (institution): Halozyme; Research grant / Funding (self), Research grant / Funding (institution): Tesaro. S.A. Piha-Paul: Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): XuanZhu; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Principa Biopharma; Research grant / Funding (institution): Helix BioPharma; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): BlueLink; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Pieris Pharmaceuticals; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Samumed. H. Park: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron. E. Garralda: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Principia Biopharma Inc.; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Genentech Inc; Research grant / Funding (institution): Loxo Oncology; Travel / Accommodation / Expenses: Menarini; Travel / Accommodation / Expenses: Glycotope; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck, Sharp & Dohme; Research grant / Funding (institution): Incyte Biosciences International; Research grant / Funding (institution): Pharma Mar, SA; Research grant / Funding (institution): Kura Oncology Inc; Research grant / Funding (institution): Macrogenics Inc; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: F. Hoffman/La Roche; Advisory / Consultancy: Ellipses Pharma; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Janssen Global Services; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Neomed Therapeutics Inc. C.J. Matheny: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. J. Carver: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. A. Moore: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. B.A. Hug: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline.