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

Journal of Translational Medicine

Protocol

Dries Reynders¹  Els Goetghebeur¹  Annabel Meireson²  Mireille Van Gele²  Daan De Maeseneer³  Sylvie Rottey⁴  Sofie Verbeke⁵  Valérie Fonteyne⁶  Katrien De Wolf⁷  Nora Sundahl⁷  Piet Ost⁸  Pieter De Visschere⁹  Karel Decaestecker^1,10  Lieve Brochez^1,11 

[1] Department of Applied Mathematics, Computer Science and Statistics and Stat-Gent CRESCENDO consortium, Ghent University, Krijgslaan 281 S9, 9000, Ghent, Belgium;Department of Dermatology and Dermatology Research Unit, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Department of Medical Oncology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Department of Medical Oncology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Cancer Research Institute Ghent (CRIG Ghent), Ghent, Belgium;Department of Pathology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Department of Radiation-Oncology and Experimental Cancer Research, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Department of Radiation-Oncology and Experimental Cancer Research, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Immuno-Oncology Network Ghent (ION Ghent), Ghent, Belgium;Department of Radiation-Oncology and Experimental Cancer Research, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Immuno-Oncology Network Ghent (ION Ghent), Ghent, Belgium;Cancer Research Institute Ghent (CRIG Ghent), Ghent, Belgium;Department of Radiology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Department of Urology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;Immuno-Oncology Network Ghent (ION Ghent), Ghent, Belgium;Cancer Research Institute Ghent (CRIG Ghent), Ghent, Belgium;Department of Dermatology and Dermatology Research Unit, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium;

关键词: Urothelial cell carcinoma;    Radiotherapy;    Immunotherapy;    Pembrolizumab;    Immunomonitoring;    Randomized clinical trial;    SBRT;    Anti-PD-1;    Bladder cancer;   

DOI  :  10.1186/s12967-017-1251-3

 received in 2017-05-17, accepted in 2017-06-21,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundCurrent 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.MethodsThe 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.DiscussionThe 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).

【 授权许可】

CC BY   
© The Author(s) 2017