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
3902 - The efficacy of preoperative breast cancer chemotherapy without anti-HER2-targeted treatment – single center experience in setting of no reimbursement in Poland (2011-2015)
Presenter: Agnieszka Badora-Rybicka
Session: Poster Display session 2
Resources:
Abstract
4733 - A Multicentre, International Neoadjuvant (NA), Randomized, Double-blind Phase III Trial comparing FULVESTRANT to a combination of FULVESTRANT and PALBOCICLIB in patients with operable Luminal Breast Cancer (SAFIA Trial)
Presenter: Jean-Marc Nabholtz
Session: Poster Display session 2
Resources:
Abstract
5227 - Outcome of Non-metastatic Male Breast Cancer: 222 patients
Presenter: Ulku Yalcintas Arslan
Session: Poster Display session 2
Resources:
Abstract
5943 - Effects of delayed initiation of adjuvant trastuzumab for non-metastatic, Her2 positive breast cancer in a limited resources setting: ML25232 study final results
Presenter: Samir Beslija
Session: Poster Display session 2
Resources:
Abstract
1725 - Final results of scalp cooling for hair preservation: A single- institution prospective study.
Presenter: Dario Loparco
Session: Poster Display session 2
Resources:
Abstract
3713 - Adjuvant Systemic Therapy in Women with Early Breast Cancer and Intermediate Prosigna ROR Scores: Is Chemotherapy Use Declining? Evidence From a Large Practice
Presenter: Lowell Hart
Session: Poster Display session 2
Resources:
Abstract
818 - Management of early breast cancer in women over 90: A 10 year experience
Presenter: Emily Coffey
Session: Poster Display session 2
Resources:
Abstract
1141 - Evolution in the risk of adverse events of adjuvant endocrine therapy in postmenopausal women with early- stage breast cancer.
Presenter: Daniel Reinhorn
Session: Poster Display session 2
Resources:
Abstract
2277 - Hepatitis B screening and incidence of flare among non-metastatic breast cancer patients treated with anthracyclines
Presenter: Zewen Zhang
Session: Poster Display session 2
Resources:
Abstract
2781 - Effect of denosumab on low bone mineral density in postmenopausal Japanese early breast cancer patients receiving aromatase nhibitors : 36-month results
Presenter: Koichi Sakaguchi
Session: Poster Display session 2
Resources:
Abstract