Poster Presentation NSW State Cancer Conference 2023

SPEAR: A Phase 2, Open-label, Single-arm Monotherapy Trial of Sulfasalazine in Pancreatic Adenocarcinoma – Trial in Progress  (#321)

Omali Pitiyarachchi 1 , Aparna Raina 1 , George Sharbeen 1 , Janet Youkhana 1 , Enmoore Lin 2 , Frank Lin 3 4 5 , Bruce Neal 2 , Jennifer Windred 2 , Vanessa Jones 2 , Keith Thornton 4 , Sarah Lynch 4 , Alex Swarbrick 4 , Tony Wang 4 , Cecilia Chang 4 , Paul Timpson 4 , Marina Pajic 4 , Astrid Magenau 4 , Sean Porazinski 4 , Gian Luca Di Tanna 2 , Talia Fuchs 6 , Jeanie Chui 4 7 , Hayley P Barker 4 , Mandy Ballinger 4 , Nimit Singhal 8 , Emily Collignon 4 , Katrin M Sjoquist 5 9 , Lorraine A Chantrill 3 10 11 , Anthony Gill 4 12 13 , David Thomas 3 4 14 , David Goldstein 3 15 , Phoebe A Phillips 1
  1. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, NSW, Australia
  2. The George Institute for Global Health, Sydney, NSW, Australia
  3. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia
  4. Garvan Institute of Medical Research, Sydney, NSW, Australia
  5. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
  6. Douglass Hanly Moir Pathology, Sydney, NSW, Australia
  7. Department of Anatomical Pathology, Royal North Shore Hospital, NSW, Australia
  8. Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia
  9. Department of Medical Oncology, St George & Sutherland Hospitals, NSW, Australia
  10. Department of Medical Oncology, Illawarra Shoalhaven Local Health District, NSW, Australia
  11. Faculty of Science, Medicine and Health, University of Wollongong, NSW, Australia
  12. Australian Pancreatic Cancer Genome Initiative (APGI), Sydney, NSW, Australia
  13. Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
  14. Centre for Molecular Oncology, UNSW Sydney, NSW, Australia
  15. Department of Medical Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital , Randwick, NSW, Australia

Objectives/Rationale: We identified SLC7A11 (cystine importer) as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC) cells and cancer associated fibroblasts (CAFs) and showed that high SLC7A11 in human PDAC stroma is independently prognostic of poor overall survival (Sharbeen et al, Cancer Res., 2021). We demonstrated that SLC7A11 inhibition in orthotopic pancreatic tumours (mice) reduced tumour growth, metastasis, and fibrosis; results validated in our human PDAC explant model (Sharbeen et al, Cancer Res., 2021). Sulfasalazine, used to treat inflammatory arthritis and ulcerative colitis, is a potent inhibitor of SLC7A11. Aim: To investigate the clinical activity of sulfasalazine in patients with PDAC and to understand the biological basis for therapeutic response using correlative science.  

 

Methods: Trial design: Phase II prospective, single-arm, open-label, monotherapy trial. Participants: 38 PDAC patients from Australian Molecular Screening and Therapeutics (MoST) Framework Protocol screening sites. Treatment: Sulfasalazine commences at 1.5g/day oral (3 evenly divided doses), then incrementally increased depending on tolerability (target dose 4.5g/day; maximum 6g/day) and continued until clinical/radiological progression or unacceptable toxicity.  Eligibility: Participants aged≥18 with advanced (Stage III unresectable/Stage IV) PDAC and presence of tumour and/or stromal SLC7A11 expression (≥1+ on 4-point scale of SLC7A11 immunohistochemistry).  Participants must have progressive disease following prior treatment with first line chemotherapy, ECOG PS 0-1, life expectancy >12 weeks, and measurable disease (RECIST v1.1).  Primary outcome: Progression-free survival at 6 months. Secondary outcomes: Objective response rate, overall survival, tolerability, health-related quality of life.  Clinical trial: ACTRN12621001347853. Correlative science: (i) Tumour sections screened for SLC7A11 by immunohistochemistry. (ii) Glutathione (biomarker of SLC7A11 inhibition) measured in blood plasma with enzymatic colorimetric assay. (iii) Spatial transcriptomics performed on tumour specimens using the Nanostring GeoMX platform (Cancer Transcriptome Atlas probes).

 

Results: 4 active sites are recruiting for SPEAR and 17 patients recommended to trial. (i) SLC7A11 has been scored in 160 samples of MoST-Pancreas, 92.8% of which had a score of ≥1+ in the tumour and/or stromal compartment and are eligible. (ii) Glutathione was detected at 86-2889µg/L in blood plasma at physiological levels. (iii) Nanostring workflow has been completed in primary PDAC and liver metastasis samples and demonstrated differentially expressed genes between relevant compartments, validating our protocol.

 

Conclusions: We have established a workflow to measure clinical and biological response to sulfasalazine in PDAC patients, and to correlate data from both parameters. The SPEAR trial will validate a therapeutic approach for PDAC that is personalised based on a stromal marker rather than genetic signature.

  1. Sharbeen G, et al. Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition. Cancer Res. 2021;81(13):3461-3479.