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

• Published in: Breast cancer research and treatment 2017-04, Vol.162 (3), p.479-488
• Main Authors: Higgins, M., Curigliano, G., Dieras, V., Kuemmel, S., Kunz, G., Fasching, P. A., Campone, M., Bachelot, T., Krivorotko, P., Chan, S., Ferro, A., Schwartzberg, L., Gillet, M., De Sousa Alves, P. M., Wascotte, V., Lehmann, F. F., Goss, P.
• Format: Article
• Language: English
• Subjects: Adjuvant chemotherapy; Antibodies; Antibodies - immunology; Antigens, Neoplasm - immunology; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Aromatase inhibitors; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer research; Cancer therapies; Cancer Vaccines; Care and treatment; Chemotherapy; Clinical Trial; Clinical trials; Combined Modality Therapy; Complications and side effects; Female; Humans; Immunotherapy; Medicine; Medicine & Public Health; Menopause; Neoadjuvant Therapy; Neoplasm Staging; Oncology; Patient safety; Postmenopausal women; Recombinant Proteins - administration & dosage; Recombinant Proteins - immunology; Safety and security measures; Treatment Outcome; Vaccination; WT1 Proteins - administration & dosage; WT1 Proteins - immunology
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4130-y

Purpose 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. Methods 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. Results 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. Conclusions 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.