BreAK CRC, a first-in-human phase I/II trial of STC-1010, a new allogenic cancer vaccine for advanced or metastatic unresectable colorectal cancer.

TPS3635 Background: Colorectal cancer (CRC) is the 3rd most common cancer worldwide. Although immunotherapy was found active in dMMR/MSI-H “hot” CRC, there is an unmet medical need for drugs likely to heat up “cold” tumors, especially for the pMMR/MSS tumors. The STC-1010 is a novel allogenic vaccine based on 2-steps modifications of established CRC cell lines, expressing native tumor specific antigens (TSA) as along with tumor-associated antigens (TAA) whose immunogenicity was increased by haptenization. Preclinical efficacy and safety results of STC-1010 murine surrogate underline the capacity of the vaccine combined with immunostimulant in low dose (cyclophosphamide and GM-CSF) associated or not with the standard of care (SoC) chemotherapy (FOLFOX or FOLFIRI) to decrease tumor volume, improve mice survival and enhance tumor T cell infiltration in different syngeneic models of mice. Ex-vivo STC-1010’s mechanism of action leads to an immune stimulation of dendritic cells and priming of CD8+ T cells inducing a massive apoptosis of CRC cells. Immunogenicity and preclinical data were confirmed using in ovoon chorio-allantoine membrane model with a significant increase of IL-12, IL-2, IFN-gamma expression in TiLs and tumor necrosis. The good safety profile in mice and no CRS harmful effects prompted the launch of the First in Human trial evaluating the STC-1010 for patients with unresectable advanced/metastatic CRC in 1 st (MSS patients) or second-line settings (MSI-H patients). Methods: The dose-escalation phase I will evaluate on 9 to 18 patients the tolerability of two STC-1010’s dose levels (3x10 6 and 6x10 6 vaccine cells) administered intra-dermally on a weekly basis for 8 weeks, followed by 4 boosts, combined with immunostimulants in low dose (oral cyclophosphamide: 50 mg/day, 3 days before vaccine and GM-CSF: 125or 250 µg, co-injected with vaccine), associated to SoC chemotherapy (mFOLFOX6 ± Bevacizumab). The primary endpoint will be the recommended phase 2 dose, while immunogenicity (T cell specific response against vaccine, delayed-Time of Hypersensitivity measurements associated to interferon-gamma dosage) will be evaluated. If no safety issue, a single-arm phase IIA- expansion cohort on 52 MSS patients and a separate cohort of 20 MSI-H patients who have progressed on SoC ICI (immune checkpoint inhibitor) will receive STC-1010 regimen with a primary outcome of rate of 12 months progression-free survival based on RECIST criteria, while the minimal residual disease will be approached by ctDNA analysis. BREAK-CRC is meant to clinically confirm the promising preclinical outcomes obtained on different syngeneic mouse models and ex-vivo assays about the potential major therapeutic impact of STC-1010 on patients with pMMR/MSS and dMMR/MSI-H ICI-resistant unresectable advanced or metastatic colorectal cancers.