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Phase 1 trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer

  • Amit Mahipal
  • Sri Harsha Tella
  • Anuhya Kommalapati
  • Gaurav Goyal
  • Heloisa Soares
  • Anthony Neuger
  • Domenico Copolla
  • Jongphil Kim
  • Richard Kim
PHASE I STUDIES

Summary

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.

Keywords

Enzalutamide Pancreatic cancer Nab-paclitaxel Gemcitabine 

Notes

Acknowledgements

Part of the work is being submitted as an abstract to 30th EORTC-NCI-AACR symposium 2018.

Funding

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

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10637_2018_676_MOESM1_ESM.docx (17 kb)
ESM 1 (DOCX 16 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Amit Mahipal
    • 1
    • 2
  • Sri Harsha Tella
    • 3
  • Anuhya Kommalapati
    • 3
  • Gaurav Goyal
    • 1
  • Heloisa Soares
    • 4
  • Anthony Neuger
    • 5
  • Domenico Copolla
    • 6
  • Jongphil Kim
    • 7
  • Richard Kim
    • 5
  1. 1.Department of Medical OncologyMayo ClinicRochesterUSA
  2. 2.Department of OncologyMayo ClinicRochesterUSA
  3. 3.Department of Internal MedicineUniversity of South Carolina School of MedicineColumbiaUSA
  4. 4.Department of OncologyUniversity of New MexicoAlbuquerqueUSA
  5. 5.Department of Gastrointestinal OncologyH. Lee Moffitt Cancer CenterTampaUSA
  6. 6.Department of Anatomic PathologyH. Lee Moffitt Cancer CenterTampaUSA
  7. 7.Department of Biostatistics and BioinformaticsH. Lee Moffitt Cancer CenterTampaUSA

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