Phase 1 trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer
Background Androgens were shown to play a key role in the growth and progression of pancreatic cancer. We evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel as a first-line treatment in advanced pancreatic cancer. Methods We used the standard 3 + 3 dose escalation design with cohort expansion to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg/day orally (phase 1a) in combination with gemcitabine and nab-paclitaxel in metastatic pancreatic cancer patients. In the expansion phase (phase 1b), AR+ was a pre-requisite criterion. We also evaluated the full pharmacokinetic (PK) profile for nab-paclitaxel and enzalutamide. Results We enrolled 24 patients, 12 patients in phase 1a and 12 patients in phase 1b. The median age was 68 (range, 32–84) years. No DLTs were observed. Grade 3/4 treatment related adverse events included neutropenia (44%), anemia (40%), leukopenia (24%), nausea and vomiting (20%), diarrhea (16%), infections (12%), thrombocytopenia (8%), thromboembolic event (8%), hypertension (8%), hypokalemia (8%), hyponatremia (8%), and ALT elevation (8%). Median overall survival and progression-free survival was 9.73 [95%CI:9.73–13.5] and 7.53 (95%CI:6.05–12.8) months, respectively. 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 h. Conclusions Enzalutamide 160 mg daily in combination with gemcitabine and nab-paclitaxel can be safely administered with no unexpected toxicities. We also noticed preliminary signals of efficacy with this combination.
KeywordsEnzalutamide Pancreatic cancer Nab-paclitaxel Gemcitabine
Part of the work is being submitted as an abstract to 30th EORTC-NCI-AACR symposium 2018.
Astellas inc provided the funding for the clinical trial. No other external funding was received.
Compliance with ethical standards
Conflict of interest
Dr. Richard Kim received honorarium from Lilly, BMS and Bayer. The other authors report no conflicts of interest for this work
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol: Off J Am Soc Clin Oncol 15(6):2403–2413. https://doi.org/10.1200/jco.1922.214.171.1243 CrossRefGoogle Scholar
- 3.Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19):1817–1825. doi: https://doi.org/10.1056/NEJMoa1011923 CrossRefGoogle Scholar
- 4.Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369 (18):1691–1703. doi: https://doi.org/10.1056/NEJMoa1304369 CrossRefGoogle Scholar
- 5.Corbishley TP, Iqbal MJ, Wilkinson ML, Williams R(1986) Androgen receptor in human normal and malignant pancreatic tissue and cell lines. Cancer 57 (10):1992–1995. https://doi.org/10.1002/1097-0142(19860515)57:10<1992::AID-CNCR2820571019>3.0.CO;2-0 CrossRefGoogle Scholar
- 11.Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen C, Higano CS, Beer TM, Hung DT, Scher HI, Jung M, Sawyers CL (2009) Development of a second-generation antiandrogen for treatment of advanced prostate Cancer. Science (New York) 324(5928):787–790. https://doi.org/10.1126/science.1168175 CrossRefGoogle Scholar
- 12.Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C, Wongvipat J (2010) Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem 53(7):2779–2796. https://doi.org/10.1021/jm901488g CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer (Oxford, England : 1990) 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026 CrossRefGoogle Scholar
- 15.Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M (2011) Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic Cancer: a phase I/II trial. J Clin Oncol 29(34):4548–4554. https://doi.org/10.1200/JCO.2011.36.5742 CrossRefGoogle Scholar
- 17.Halm U, Schumann T, Schiefke I, Witzigmann H, Mossner J, Keim V (2000) Decrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer. Br J Cancer 82(5):1013–1016. https://doi.org/10.1054/bjoc.1999.1035 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Ziske C, Schlie C, Gorschluter M, Glasmacher A, Mey U, Strehl J, Sauerbruch T, Schmidt-Wolf IG (2003) Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine. Br J Cancer 89(8):1413–1417. https://doi.org/10.1038/sj.bjc.6601263 CrossRefPubMedPubMedCentralGoogle Scholar