Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study.
This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms' tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients.



Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab-chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A-C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination.



Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely.



Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab-chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves.
Department of Medical Oncology, Mater Misericordiae University Hospital, Eccles St., Dublin, 7, Ireland. mhiggins@mater.ie.
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0000-0001-5018-3026
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Higgins
Division of Early Drug Development, Istituto Europeo di Oncologia, Milan, Italy.
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Curigliano
Clinical Investigational Unit, Institut Curie, Paris, France.
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Dieras
Breast UnitKliniken Essen-Mitte, Essen, Germany.
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Kuemmel
Department of Obstetrics & Gynecology, St.-Johannes-Hospital, Dortmund, Germany.
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Kunz
Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-EMN, Erlangen, Germany.
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Fasching
Service d'Oncologie Médicale, Institut de Cancérologie de l'Ouest, Saint Herblain, France.
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Campone
Department of Medical Oncology, Centre Leon Berard, Lyon, France.
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Bachelot
Petrov Research Institute of Oncology, St. Petersburg, Russian Federation.
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Krivorotko
Department of Clinical Oncology, Nottingham University Hospital NHS Trust (City campus), Nottingham, UK.
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Chan
Unit of Medical Oncology, Santa Chiara Hospital, Trento, Italy.
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Ferro
Division of Hematology/Oncology, University of Tennessee Health Science Center, The West Clinic, Medical Oncology, Memphis, USA.
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Schwartzberg
GSK Vaccines, Rixensart, Belgium.
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Gillet
GSK Vaccines, Rixensart, Belgium.|Celyad, Mont-Saint-Guibert, Belgium.
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De Sousa Alves
GSK Vaccines, Rixensart, Belgium.
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Wascotte
GSK Vaccines, Rixensart, Belgium.|Celyad, Mont-Saint-Guibert, Belgium.
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Lehmann
MGH Cancer Center, Massachusetts General Hospital, Boston, USA.
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Goss
D000906:Antibodies / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007167:Immunotherapy; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000276:immunology; D016896:Treatment Outcome; D025721:WT1 Proteins / Q000008:administration & dosage* / Q000276:immunology
D000906:Antibodies; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D011994:Recombinant Proteins; D025721:WT1 Proteins
Breast cancer; Immunogenicity; Immunotherapy; Neoadjuvant therapy; Safety; WT1 antigen