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Poster Display session 2

5124 - STAR_PAC: Phase I clinical trial repurposing all trans retinoic acid (ATRA) as stromal targeting agent in a novel drug combination for pancreatic cancer. 

Date

29 Sep 2019

Session

Poster Display session 2

Topics

Tumour Site

Pancreatic Adenocarcinoma

Presenters

Hemant Kocher

Citation

Annals of Oncology (2019) 30 (suppl_5): v253-v324. 10.1093/annonc/mdz247

Authors

H.M. Kocher1, B. Basu2, F.E.M. Froeling3, D. Sarker4, S. Slater5, D. Carlin6, C. Coetzee1, N. de Souza6, M. Goulart1, C. Hughes1, A. Imrali1, C. Lawrence1, K. Mousa7, B. North1, A. Prendergast1, R. Roberts1, P. Sasieni8, D. Propper5

Author affiliations

  • 1 Barts Cancer Institute, QMUL, EC1M 6BQ - London/GB
  • 2 Oncology, Cambridge University Hospitals NHS Foundation Trust - Addenbrooke's Hospital, CB2 0QQ - Cambridge/GB
  • 3 Department Of Surgery And Cancer, Imperial College London - Hammersmith Hospital, W12 0HS - London/GB
  • 4 Oncology, Guy's and St. Thomas' Hospital NHS Trust, SE1 9RT - London/GB
  • 5 Oncology, Barts Health NHS Trust, EC1A 7BE - London/GB
  • 6 Imaging, The Institute of Cancer Research, London, SW3 6JB - London/GB
  • 7 Barts Cancer Institute, Queen Mary University, EC1M6BQ - London/GB
  • 8 Kings Clinical Trials Unit, Kings College London, WC2R 2LS - London/GB

Resources

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Abstract 5124

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.

Clinical trial identification

Editorial acknowledgement

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.

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