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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

Nora Sundahl (UGent) , Katrien De Wolf (UGent) , Sylvie Rottey (UGent) , Karel Decaestecker (UGent) , Daan De Maeseneer (UGent) , Annabel Meireson (UGent) , Els Goetghebeur (UGent) , Valerie Fonteyne (UGent) , Sofie Verbeke (UGent) , Pieter De Visschere (UGent) , et al.
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Organization
Abstract
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.
Keywords
BLADDER-CANCER, SINGLE-ARM, THERAPY, MULTICENTER, COMBINATION, CISPLATIN, RADIATION, METHOTREXATE, VINBLASTINE, DOXORUBICIN, Urothelial cell carcinoma, Radiotherapy, Immunotherapy, Pembrolizumab, Immunomonitoring, Randomized clinical trial, SBRT, Anti-PD-1, Bladder, cancer

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Chicago
Sundahl, Nora, Katrien De Wolf, Sylvie Rottey, Karel Decaestecker, Daan De Maeseneer, Annabel Meireson, Els Goetghebeur, et al. 2017. “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 15.
APA
Sundahl, N., De Wolf, K., Rottey, S., Decaestecker, K., De Maeseneer, D., Meireson, A., Goetghebeur, E., et al. (2017). 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, 15.
Vancouver
1.
Sundahl N, De Wolf K, Rottey S, Decaestecker K, De Maeseneer D, Meireson A, et al. 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. 2017;15.
MLA
Sundahl, Nora, Katrien De Wolf, Sylvie Rottey, et al. “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 15 (2017): n. pag. Print.
@article{8545944,
  abstract     = {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.},
  articleno    = {150},
  author       = {Sundahl, Nora and De Wolf, Katrien and Rottey, Sylvie and Decaestecker, Karel and De Maeseneer, Daan and Meireson, Annabel and Goetghebeur, Els and Fonteyne, Valerie and Verbeke, Sofie and De Visschere, Pieter and Reynders, Dries and Van Gele, Mireille and Brochez, Lieve and Ost, Piet},
  issn         = {1479-5876},
  journal      = {JOURNAL OF TRANSLATIONAL MEDICINE},
  keyword      = {BLADDER-CANCER,SINGLE-ARM,THERAPY,MULTICENTER,COMBINATION,CISPLATIN,RADIATION,METHOTREXATE,VINBLASTINE,DOXORUBICIN,Urothelial cell carcinoma,Radiotherapy,Immunotherapy,Pembrolizumab,Immunomonitoring,Randomized clinical trial,SBRT,Anti-PD-1,Bladder,cancer},
  language     = {eng},
  pages        = {9},
  title        = {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},
  url          = {http://dx.doi.org/10.1186/s12967-017-1251-3},
  volume       = {15},
  year         = {2017},
}

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