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Phase II study of the antibody-drug conjugate TAK-264 (MLN0264) in patients with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing guanylyl cyclase C

  • PHASE II STUDIES
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Summary

Background The first-in-class antibody–drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility. Adult patients with gastric and gastroesophageal junction adenocarcinoma expressing low, intermediate, or high GCC levels received TAK-264 1.8 mg/kg as a 30-min intravenous infusion once every 21 days, for up to 1 year. The primary endpoint was objective response rate. Radiographic assessments of tumor burden were performed every 2 cycles (6 weeks). Results A total of 38 patients participated in the study. Patients received a median of 2 (range 1–14) cycles; 8 (21%) received at least 6 cycles. The most common adverse events were nausea (53%), fatigue (32%), and decreased appetite (29%). Grade ≥3 events including anemia, diarrhea, and neutropenia were seen in 14 (37%) patients. Systemic exposure to TAK-264 was maintained throughout each treatment cycle. Two patients (6%) with intermediate GCC expression had objective responses. Conclusions TAK-264 demonstrated a manageable safety profile in this patient population. The stage I interim analysis did not support continuation to stage II of the study.

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Acknowledgements

The authors acknowledge JungAh Jung and Timothy Wyant for statistical and translational input. The authors also acknowledge Yosef Mansour and Tamara Bailey of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript.

Author contributions

All authors contributed to the study design, conduct or collection, the writing and reviewing of the manuscript, and approved the final manuscript for submission.

Author information

Authors and Affiliations

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

    Khaldoun Almhanna

  2. Hospital Universitario Virgen del Rocio, Seville, Spain

    Maria Luisa Limon Miron

  3. Florida Cancer Specialists, Tampa, FL, USA

    David Wright

  4. HM Universitario Sanchinarro, CIOCC, Madrid, Spain

    Antonio Cubillo Gracian

  5. The Christie NHS Foundation Trust, Manchester, UK

    Richard A. Hubner

  6. Erasme University Hospital, Brussels, Belgium

    Jean-Luc Van Laethem

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

    Carolina Muriel López

  8. Vall d’Hebron University Hospital and VHIO-Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Maria Alsina

  9. Ramon y Cajal University Hospital, Madrid, Spain

    Frederico Longo Muñoz

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

    Johanna Bendell

  11. The Christ Hospital Physicians, Cincinnati, OH, USA

    Irfan Firdaus

  12. University of Colorado, Denver, CO, USA

    Wells Messersmith

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

    Zhan Ye, Adedigbo A. Fasanmade, Hadi Danaee & Thea Kalebic

Authors
  1. Khaldoun Almhanna
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  2. Maria Luisa Limon Miron
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  6. Jean-Luc Van Laethem
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  7. Carolina Muriel López
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  8. Maria Alsina
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  9. Frederico Longo Muñoz
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  11. Irfan Firdaus
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  12. Wells Messersmith
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  13. Zhan Ye
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  14. Adedigbo A. Fasanmade
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  15. Hadi Danaee
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  16. Thea Kalebic
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Corresponding author

Correspondence to Khaldoun Almhanna.

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Conflict of interest

Disclosures are as follows. Khaldoun Almhanna: Lilly advisor/board member, Genentech speaker’s bureau. Richard A. Hubner: Eli Lilly advisory board member. Wells Messersmith: Research support from Millennium. Zhan Ye, Adedigbo A. Fasanmade, Hadi Danaee and Thea Kalebic: full-time employees of Millennium. Maria Luisa Limon Miron, David Wright, Antonio Cubillo Gracian, Jean-Luc Van Laethem, Carolina Muriel López, Maria Alsina, Frederico Longo Muñoz, Johanna Bendell, and Irfan Firdaus: nothing to disclose.

Ethical approval

This study was conducted according to the principles set out in the Declaration of Helsinki, in compliance with International Conference on Harmonisation, Good Clinical Practice guidelines, and local regulatory requirements. Institutional review boards/ethics committees at the participating investigational centers approved the study.

Informed consent

Written informed consent was obtained from all individual patients included in the study.

Funding

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

Electronic supplementary material

Supplementary Fig. S1

The 600 H-score is based on the sum of the 0–300 H-score for cytoplasmic staining and the 0–300 H-score for apical staining in order to capture both the apical (black) and cytoplasmic (white) localization of GCC-positive staining (PDF 805 kb)

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Almhanna, K., Miron, M.L.L., Wright, D. et al. Phase II study of the antibody-drug conjugate TAK-264 (MLN0264) in patients with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing guanylyl cyclase C. Invest New Drugs 35, 235–241 (2017). https://doi.org/10.1007/s10637-017-0439-y

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