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Investigational New Drugs

, Volume 35, Issue 5, pp 634–641 | Cite as

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

  • Khaldoun AlmhannaEmail author
  • David Wright
  • Teresa Macarulla Mercade
  • Jean-Luc Van Laethem
  • Antonio Cubillo Gracian
  • Carmen Guillen-Ponce
  • Jason Faris
  • Carolina Muriel Lopez
  • Richard A. Hubner
  • Johanna Bendell
  • Alain Bols
  • Jaime Feliu
  • Naureen Starling
  • Peter Enzinger
  • Devalingham Mahalingham
  • Wells Messersmith
  • Huyuan Yang
  • Adedigbo Fasanmade
  • Hadi Danaee
  • Thea Kalebic
PHASE II STUDIES

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.

Keywords

Phase II trials_Pancreatic cancers: Pancreas Antibody immunotherapy Antibodies/immunoconjugates Guanylyl cyclase C Antibody–drug conjugate TAK-264 

Notes

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.

Compliance with ethical standards

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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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Khaldoun Almhanna
    • 1
    Email author
  • David Wright
    • 2
  • Teresa Macarulla Mercade
    • 3
  • Jean-Luc Van Laethem
    • 4
  • Antonio Cubillo Gracian
    • 5
    • 6
  • Carmen Guillen-Ponce
    • 7
  • Jason Faris
    • 8
  • Carolina Muriel Lopez
    • 9
  • Richard A. Hubner
    • 10
  • Johanna Bendell
    • 11
  • Alain Bols
    • 12
  • Jaime Feliu
    • 13
  • Naureen Starling
    • 14
  • Peter Enzinger
    • 15
  • Devalingham Mahalingham
    • 16
  • Wells Messersmith
    • 17
  • Huyuan Yang
    • 18
  • Adedigbo Fasanmade
    • 18
  • Hadi Danaee
    • 18
  • Thea Kalebic
    • 18
  1. 1.Department of Gastrointestinal OncologyMoffitt Cancer CenterTampaUSA
  2. 2.Florida Cancer SpecialistsTampaUSA
  3. 3.Vall d’Hebron University HospitalBarcelonaSpain
  4. 4.Erasme University HospitalBrusselsBelgium
  5. 5.HM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal (CIOCC)MadridSpain
  6. 6.Departamento de Ciencias Médicas ClínicasUniversidad San Pablo CEUMadridSpain
  7. 7.Ramón y Cajal University HospitalMadridSpain
  8. 8.Massachusetts General Hospital Cancer CenterBostonUSA
  9. 9.Hospital Universitario Virgen de la VictoriaMálagaSpain
  10. 10.The Christie NHS Foundation TrustManchesterUK
  11. 11.Sarah Cannon Research Institute/Tennessee OncologyNashvilleUSA
  12. 12.Brugge Oostende Oncologisch CentrumBrugesBelgium
  13. 13.CIBERONCLa Paz University HospitalMadridSpain
  14. 14.The Royal Marsden NHS Foundation TrustLondonUK
  15. 15.Dana Farber Cancer InstituteBostonUSA
  16. 16.University of Texas Health Science CenterSan AntonioUSA
  17. 17.University of ColoradoAuroraUSA
  18. 18.Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company LimitedCambridgeUSA

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