A phase I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent pembrolizumab in metastatic urothelial carcinoma: evaluation of safety and clinical and immunologic response
| Autor: | Daan De Maeseneer, Pieter De Visschere, Sylvie Rottey, Els Goetghebeur, Karel Decaestecker, Piet Ost, Sofie Verbeke, Valérie Fonteyne, Dries Reynders, Nora Sundahl, Mireille Van Gele, Annabel Meireson, Katrien De Wolf, Lieve Brochez |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Oncology medicine.medical_treatment Statistics as Topic MULTICENTER lcsh:Medicine Pembrolizumab THERAPY law.invention 0302 clinical medicine Randomized controlled trial law Protocol Medicine and Health Sciences SINGLE-ARM Neoplasm Metastasis SBRT Bladder cancer Combination chemotherapy General Medicine Combined Modality Therapy Anti-PD-1 METHOTREXATE Mathematics and Statistics 030220 oncology & carcinogenesis Female Immunotherapy Randomized clinical trial Urologic Neoplasms medicine.medical_specialty DOXORUBICIN Metastatic Urothelial Carcinoma Combination therapy Bladder BLADDER-CANCER Urothelial cell carcinoma Antibodies Monoclonal Humanized Radiosurgery General Biochemistry Genetics and Molecular Biology CISPLATIN 03 medical and health sciences Internal medicine medicine Humans cancer VINBLASTINE COMBINATION Immune-Related Response Criteria Radiotherapy business.industry lcsh:R Dose-Response Relationship Radiation medicine.disease Radiation therapy Immunomonitoring 030104 developmental biology Sample Size RADIATION Urothelium business Follow-Up Studies |
| Zdroj: | Journal of Translational Medicine, Vol 15, Iss 1, Pp 1-9 (2017) JOURNAL OF TRANSLATIONAL MEDICINE Journal of Translational Medicine |
| ISSN: | 1479-5876 |
| DOI: | 10.1186/s12967-017-1251-3 |
| Popis: | Background Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates. Methods The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon’s two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment. Discussion The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564). Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1251-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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