Journal Article

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

Kunz, G., Gillet, M., Schwartzberg, L., Lehmann, F. F., Kuemmel, S., Dieras, V., De Sousa Alves, P. M., Goss, P., Campone, M., Krivorotko, P., Wascotte, V., Fasching, P. A., Higgins, M., Curigliano, G., Ferro, A., Bachelot, T., Chan, S.

2017

Overview

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.

• Publisher: Springer US,Springer,Springer Nature B.V
• Subject: 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