TACTICAL: A phase I/II trial to assess the safety and efficacy of MSCTRAIL in the treatment of metastatic lung adenocarcinoma.

Abstract

TPS9116 Background: Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma allowing them to act as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells however short biological half-life has its limited therapeutic efficacy. We have transduced umbilical cord MSCs with a lentiviral vector to express TRAIL (MSCTRAIL). These cells trigger apoptosis selectively in cancer cells with evidence of synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are delivering ex vivo pooled MSCTRAIL from third party donors without tissue matching or immunosuppression. Efficacy has been demonstrated using in vitro co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1]. Methods: TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment naïve patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1. Phase I is a dose de-escalation study, patients receive SOC on day 1 and 4x108 MSCTRAIL cells on day 2 of a 21 day cycle for 3 cycles. A Bayesian adaptive design will recommend dose reductions if excessive toxicities occur. Primary outcomes are to determine recommended phase II dose along with safety and tolerability of MSCTRAIL. 46 patients will then be randomised into a multi-centre phase II double blind, placebo-controlled trial to receive SOC and either MSCTRAIL or placebo (1:1). Primary outcome is tumour response rate by RECIST (v 1.1) criteria at 12 weeks. Secondary outcomes include, best overall response, duration of response, progression free survival and overall survival. TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC therapy in cancer. 1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42. Clinical trial information: NCT03298763.