Abstract B28: Phase I trial of gemcitabine, nab-paclitaxel and enzalutamide for treatment of advanced pancreatic cancer
Authors: Mahipal Amit , Springett Gregory , Burke Nancy , Neuger Anthony , Copolla Domenico , Kim Richard 
Published: May 2016

Abstract
Background: Androgens may play an important role in the growth and progression of pancreatic cancer. In this Phase I trial, we evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer as a first-line treatment.
Methods: Standard 3+3 dose escalation design with cohort expansion was used to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg oral daily. In the expansion phase, AR+ was required as pre-screening criteria. Gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) was administered IV on days 1, 8 and 15 of a 28-day cycle. The dose limiting toxicity (DLT) period was 28-days or until the beginning of the second cycle for the phase Ia part. A full pharmacokinetic (PK) profile was evaluated for nab-paclitaxel after the initial dose through 48 hours post dose while enzalutamide was tested on day 1 at 1 and 2 hours post dose along with levels every 7 days to follow achievement of steady state by day 29 (Cycle 2 Day 1).
Results: Nineteen patients with stage IV pancreatic cancer were enrolled in this trial, 5 patients at the first dose level and 13 patients at the second dose level, including 6 patients in dose expansion. The median age was 65 years (51-82 years). Two patients were female. In the phase 1b/expansion part, 7 out of 19 (37%) patients were positive for AR. Common site of metastases were liver (11), LN (8) and lung (5). No DLTs were observed. Grade 3/4 treatment related adverse events included neutropenia (32%), anemia (32%), leukopenia (21%), thrombocytopenia (11%), infections (11%), febrile neutropenia (5%), ALT elevation (5%), pneumonitis (5%), diarrhea (5%), skin infection (5%) and hypoxia (5%). Among the 15 evaluable patients, 2 (13%) patients had partial response and 13 (87%) patients had stable disease. All patients with stable disease had initial decrease in target lesions. All patients had decreases in CA 19-9 levels with the median decrease of 1032 U/L.
PK analysis suggests that the combination therapy does not impact the kinetics of either drug evaluated. Enzalutamide reached steady state levels between day 22 and 29 and the mean half-life of nab-paclitaxel was 19.6 ± 4.7 hours. All other PK parameters estimates are similar to historical data.
Conclusions: Enzalutamide at the dose of 160 mg daily can be safely administered in combination with gemcitabine and nab-paclitaxel. No unexpected toxicity has been observed. Preliminary signals of efficacy were observed with this combination. Patients with AR+ tumors continue to being enrolled in phase 1b part.
Citation Format: Amit Mahipal, Gregory Springett, Nancy Burke, Anthony Neuger, Domenico Copolla, Richard Kim. Phase I trial of gemcitabine, nab-paclitaxel and enzalutamide for treatment of advanced pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B28.