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

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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.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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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.

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Authors and Affiliations

  1. Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA

    Amit Mahipal & Gaurav Goyal

  2. Department of Oncology, Mayo Clinic, 200 1st street SW, Rochester, MN, 55906, USA

    Amit Mahipal

  3. Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, SC, USA

    Sri Harsha Tella & Anuhya Kommalapati

  4. Department of Oncology, University of New Mexico, Albuquerque, NM, USA

    Heloisa Soares

  5. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Anthony Neuger & Richard Kim

  6. Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Domenico Copolla

  7. Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Jongphil Kim

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  1. Amit Mahipal
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  9. Richard Kim
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Correspondence to Amit Mahipal.

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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.

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

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Mahipal, A., Tella, S.H., Kommalapati, A. et al. Phase 1 trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer. Invest New Drugs 37, 473–481 (2019). https://doi.org/10.1007/s10637-018-0676-8

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