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

• DOI: 10.1007/s10549-017-4130-y
• Publication Date: 2017-02-07T02:19:21Z
• Authors: M. Higgins; G. Curigliano; V. Dieras; S. Kuemmel; G. Kunz; P. A. Fasching; M. Campone; T. Bachelot; P. Krivorotko; S. Chan; A. Ferro; L. Schwartzberg; M. Gillet; P. M. De Sousa Alves; V. Wascotte; F. F. Lehmann; P. Goss
• Keywords: Cancer Research; Medizin; Breast Neoplasms; Breast cancer; Immunogenicity; Immunotherapy; Neoadjuvant therapy; Safety; WT1 antigen; Oncology; Cancer Research; Clinical Trial; Cancer Vaccines; Combined Modality Therapy; Antibodies; Neoadjuvant Therapy; Recombinant Proteins; 3. Good health; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Oncology; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Humans; Female; Immunotherapy; WT1 Proteins; Neoplasm Staging

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.