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Background Triple Negative Breast Cancer (TNBC) represents approximately 15% of all breast cancer. It confers a poorer prognosis relative to the other breast cancer subtypes, with an increased likelihood of recurrence and death within 5 years of diagnosis. There is no standard of care specifically for patients presenting with TNBC. Altered amino acid metabolism have been shown to play a role in TNBC. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. In a recent randomized phase 2b study, eryaspase has demonstrated evidence of improved overall survival (OS) and progression free survival (PFS) and acceptable safety when combinedwith gemcitabine or FOLFOX therapyinpatients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). The demonstration of ASNase activity of eryaspase in combination with chemotherapy including DNA-damaging agents in both preclinical and clinical settings provide a rationale to further test combination in TNBC. Trial design TRYbeCA-2 is an international, randomized, open-label phase 2/3 trial (N = 64 for phase 2) of eryaspase combined with chemotherapy in patients with locally recurrent or metastatic TNBC who have not received prior systemic therapy for locally recurrent or metastatic disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/carboplatin with or without eryaspase, administered as IV infusion on Day 1 and Day 8 of each 3-week cycle. Key eligibility criteria include measurable lesion(s), performance status 0 or 1, and adequate organ function. The primary endpoint is the objective response rate (ORR) as determined by an independent radiological review. Key secondary endpoints include ORR as determined by the investigator’s assessment, clinical benefit rate, overall survival, progression-free survival, safety, biomarker research, pharmacokinetics and pharmacodynamics. Clinical trial identification NCT03674242. Legal entity responsible for the study Erytech. Funding Erytech. Disclosure J. Bertrand: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. A. Clermont: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. R. Pollard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. R. Chrestia-Blanchine: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. N. Biswas-Baldwin: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. I. El-Hariry: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. All other authors have declared no conflicts of interest.

Background Preclinical data demonstrated that we can effectively target pancreatic stellate cells, with measurement of subsequent changes within the stroma, using all trans retinoic acid (ATRA). In a phase I trial we have repurposed ATRA as a stromal targeting agent in combination with gemcitabine and nab-paclitaxel (G-nP). Methods Patients with locally advanced or metastatic pancreatic cancer, who had not received prior systemic therapy for their disease, were eligible. The primary objectives were to determine the maximum tolerated dose (MTD) and the optimal biological dose (OBD) of ATRA in combination with G-nP. Secondary objectives were to evaluate safety and tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of this combination. An accelerated titration design by the Bayesian Continuous Reassessment Method was used to determine the MTD. Results Between Feb2016 and Feb2017, four UK centres enrolled 18 patients; between Jul2017 and Feb2018, two UK centres enrolled a further 10 patients who were treated at the MTD to ascertain the OBD. Most (24/28) patients had metastatic disease. The MTD and recommended phase 2 dose (RP2D) was gemcitabine (1000mg/m2 iv), nab-paclitaxel (125mg/m2 iv) both on days 1,8 and 15 of each 28 day cycle and ATRA (45 mg/m2 orally) in two divided doses from days 1 to 15 of each cycle. Dose limiting toxicities occurred in 2 patients (thrombocytopenia). The most common ≥ Grade 3 toxicities were asthenia (n = 3), diarrhoea (n = 2), neutropenia (n = 2), peripheral neuropathy (n = 2) and infection (n = 2) in RP2D treated patients (n = 19). Exploratory analysis showed median overall survival for RP2D treated patients receiving at least 2 cycles of chemotherapy or progressing within the first 2 cycles (n = 15) was 11.66 months (95%CI 8.57-15.67), better compared to 8.5 (95%CI 7.9-9.5) months for G-nP in the MPACT trial (Von Hoff NEJM 2013). Pharmacodynamic data from DW-MRI, tissue and serum protein expression are suggestive of stromal modulation. Conclusions Addition of ATRA as a stromal targeting agent to G-nP combination therapy is safe, tolerable. G-nP-ATRA will now be explored in a phase II randomised controlled trial for locally advanced pancreatic cancer. Legal entity responsible for the study Barts Health NHS Trust. Funding Medical Research Council (MRC), Celgene. Disclosure All authors have declared no conflicts of interest.