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A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C

  • PHASE II STUDIES
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Summary

Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1–10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

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Acknowledgements

The authors acknowledge Sabah Farooq of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc. ADC technology was licensed from Seattle Genetics, Inc.

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Authors and Affiliations

  1. Department of Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA

    Khaldoun Almhanna

  2. Florida Cancer Specialists, Tampa, FL, USA

    David Wright

  3. Vall d’Hebron University Hospital, Barcelona, Spain

    Teresa Macarulla Mercade

  4. Erasme University Hospital, Brussels, Belgium

    Jean-Luc Van Laethem

  5. HM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain

    Antonio Cubillo Gracian

  6. Departamento de Ciencias Médicas Clínicas, Universidad San Pablo CEU, Madrid, Spain

    Antonio Cubillo Gracian

  7. Ramón y Cajal University Hospital, Madrid, Spain

    Carmen Guillen-Ponce

  8. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Jason Faris

  9. Hospital Universitario Virgen de la Victoria, Málaga, Spain

    Carolina Muriel Lopez

  10. The Christie NHS Foundation Trust, Manchester, UK

    Richard A. Hubner

  11. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA

    Johanna Bendell

  12. Brugge Oostende Oncologisch Centrum, Bruges, Belgium

    Alain Bols

  13. CIBERONC, La Paz University Hospital, Madrid, Spain

    Jaime Feliu

  14. The Royal Marsden NHS Foundation Trust, London, UK

    Naureen Starling

  15. Dana Farber Cancer Institute, Boston, MA, USA

    Peter Enzinger

  16. University of Texas Health Science Center, San Antonio, TX, USA

    Devalingham Mahalingham

  17. University of Colorado, Aurora, CO, USA

    Wells Messersmith

  18. Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

    Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee & Thea Kalebic

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  1. Khaldoun Almhanna
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Corresponding author

Correspondence to Khaldoun Almhanna.

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Conflicts of interest

Khaldoun Almhanna: Lilly advisor/board member, Genentech Speaker’s bureau. Jason Faris: Current employee of Novartis; consultant for Merrimack Pharmaceuticals and N-of-One Therapeutics; research for Exelixis, Millennium, Agios, and Roche/Genentech. Richard A. Hubner: Advisory Board payments from Celgene and BTG. Jaime Feliu: Advisor/honoraria for Sanofi, Amgen, Bayer, Lilly. Peter Enzinger; Speaker’s bureau for Merck esophageal cancer. Devalingham Mahalingham: Advisory board for Bayer, Baxalta, and Genspera; Speaker bureau for Genentech, Amgen, and Bayer. Wells Messersmith: Research support from Millennium. Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee, Thea Kalebic: Employees of Millennium. David Wright, Teresa Macarulla Mercade, Jean-Luc Van Laethem, Antonio Cubillo Gracian, Carmen Guillen-Ponce, Carolina Muriel Lopez, Johanna Bendell, Alain Bols, Naureen Starling: nothing to disclose.

Funding

This study was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Ethical approval

The institutional review boards and independent ethics committees reviewed all appropriate study documentation to safeguard the rights, safety, and well-being of the patients. Written informed consent was obtained from each patient prior to initiating study participation, in compliance with International Conference on Harmonisation-Good Clinical Practices guidelines, the principles set out in the Declaration of Helsinki, and all applicable regulatory requirements.

Informed consent

The study was conducted in compliance with the protocol, Good Clinical Practices, applicable regulatory requirements, and International Conference on Harmonisation guidelines.

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Almhanna, K., Wright, D., Mercade, T.M. et al. A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C. Invest New Drugs 35, 634–641 (2017). https://doi.org/10.1007/s10637-017-0473-9

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