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.
Resources from the same session
3006 - Nal-iri/lv5-fu versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (OESIRI-PRODIGE 62): A FFCD multicenter, randomized, phase II study.
Presenter: Violaine Randrian
Session: Poster Display session 2
Resources:
Abstract
3697 - The expression of Versican and its role in pancreatic neuroendocrine tumor
Presenter: Zhao Sun
Session: Poster Display session 2
Resources:
Abstract
6073 - Characteristics of patients with thyroid carcinoma in the united states
Presenter: Dina El-Habashy
Session: Poster Display session 2
Resources:
Abstract
2124 - The discrimination of pituitary adenomas and craniopharyngioma on MRI: from image features to texture features
Presenter: Hanyue Xu
Session: Poster Display session 2
Resources:
Abstract
3786 - Proportion of Peripheral Lymphocyte Subsets Correlates with the Progression-free Survival and Metastatic Status of Pancreatic Neuroendocrine Tumor Patients
Presenter: Yitao Gong
Session: Poster Display session 2
Resources:
Abstract
2263 - Immunohistochemical expression of ER-α and PR in papillary thyroid carcinoma
Presenter: Enas Elkhouly
Session: Poster Display session 2
Resources:
Abstract
4386 - SILVELUL Project: Immunohistochemical panel analyses as potential predictive and prognostic factors in Pancreatic Neuroendocrine Tumors (PanNET) Treated with CAPTEM or Everolimus
Presenter: Ana De Jesus-Acosta
Session: Poster Display session 2
Resources:
Abstract
2302 - Carcinoid heart disease (CHD): the CRUSOE-NETs, a prospective cohort study from the French Group of Endocrine Tumors (GTE)
Presenter: Kathleen Dekeister Geoffroy
Session: Poster Display session 2
Resources:
Abstract
5749 - Safety of high doses of somatostatin analogs in well differentiated NENs in elderly
Presenter: Massimiliano Cani
Session: Poster Display session 2
Resources:
Abstract
3931 - Differences in multikinase inhibitors (MKI) toxicity profile according to gender. A pooled analysis of three phase II trials with lenvatinib, pazopanib and sorafenib in patients (pts) with advanced gastroenteropancreatic (GEP) neuroendocrine tumors (NETs).
Presenter: Jorge Hernando Cubero
Session: Poster Display session 2
Resources:
Abstract