The aim of this study is to evaluate the efficacy and safety of PARP Inhibition and programmed cell death protein-1 (PD-1) blockade immunotherapy with concurrent stereotactic body radiotherapy (SBRT) for metastatic or advanced bone and soft tissue sarcoma.
Bone and soft tissue sarcomas are a group of highly heterogeneous malignant tumors that originate from mesenchymal tissue. The recurrent and metastatic sarcomas are usually refractory to traditional radiotherapy and chemotherapy, with a five-year survival rate is less than 20% to 30%. Therefore, novel therapy targeting the molecular phenotypic characteristics of bone and soft tissue sarcomas and conduct personalized and precise treatment for specific target patient subgroups is one of the important directions in the current clinical and translational fields. Studies based on the anti-cancer mechanism of synthetic lethality have shown that tumor cells with BRCA1 or BRCA2 gene mutations are very sensitive to the action of PARP inhibitors. Interestingly, recent research results have shown that many other tumor types besides gynecological tumors can also exhibit BRCA-like phenotypes (BRCAness) and genomic instability (GI). Among them, BRCAness is a subtype of bone and soft tissue sarcoma with poor prognosis. Although such patients rarely carry BRCA gene mutations, they can still potentially benefit from treatment with drugs related to DNA damage and synthetic lethality, such as PARP inhibitors. In addition, the latest research shows that the BRCA-like phenotype in sarcoma is related to immunosuppression in its tumor microenvironment and targeted intervention of the PARP pathway is likely to have a potential immune sensitizing effect on the tumor microenvironment of sarcoma. Our previous study based on 264 samples also suggested that in sarcoma subtypes with genomic complexity, tumor cells often demonstrated high GI characteristics, and the corresponding tumor transcriptomes exhibited BRCAness. Furthermore, the investigators established 8 cases of patient-derived sarcoma primary cell model (PTCC) through tumor biopsy samples and observed a high sensitivity to DNA damage in sarcoma habouring BRCAness. In recent years, studies have found that when radiotherapy is given to local tumor lesions, Abscopal effect could be elicited by the immunogenic death of the local tumor. The investigators recently reviewed the clinical prognosis of 44 patients with advanced bone and soft tissue sarcoma treated with stereotactic body radiation therapy (SBRT) in our institute and found that the tumor response rate to the immune checkpoint inhibitor appears to be significantly increased after SBRT. Based on these findings, the investigators speculate that the combination of SBRT and PARP inhibition regimens could potentially boost the immunogenic death and further improve the immunotherapy response in metastatic or advanced sarcomas. In this clinical trial, the investigators aim to evaluate the efficacy and safety of PARP Inhibition and programmed cell death protein-1 (PD-1) blockade immunotherapy with concurrent stereotactic body radiotherapy (SBRT) for metastatic or advanced bone and soft tissue sarcoma as a phase II clinical study. Meanwhile, the investigators evaluated the patient's tumor gene mutation, homologous recombination deficiency (HRD) score, and RAD51 functional testing and other aspects for correlative biomarker exploration, providing a theoretical basis for molecular precision treatment of bone and soft tissue sarcoma with PARP inhibitiors.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
86
Patients receive Camrelizumab (PD-1 inhibitor) and fluzoparib (PARP inhibitor) with concurrent stereotactic body radiotherapy (SBRT)
Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine
Shanghai, Shanghai Municipality, China
RECRUITING6-momth progression-free survival rate (6m-PFSR)
The proportion of patients that are progression-free according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), defined as the ratio of patients who have not died or progressed (CR+PR+SD) over the total number of subjects recruited.
Time frame: 6 months from recruitment
Objective respones rate (ORR)
Defined as the number of subjects with a best response of (CR+PR)/total number of subjects\*100% based on RECISTv1.1 and irRECIST standards respectively
Time frame: From baseline to disease progression or death, whichever occurs first, until 3 years after accrual
Disease control rate (DCR)
Defined as the number of subjects with a best response of (CR+PR+SD)/total number of subjects\*100% based on RECISTv1.1 and irRECIST standards respectively;
Time frame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual
Duration of response (DOR)
Defined as the interval from first time of response (CR or PR) until disease progression (PD) according to RECISTv1.1 and irRECIST standards respectively, and estimated by the Kaplan-Meier method, including median, Interquartiles and 95% confidence intervals
Time frame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual
Progression-free survival (PFS)
Defined as the time from receiving the first study drug to the death or relapse of the subject, assessed by RECISTv1.1 and irRECIST standards respectively, and estimated by the Kaplan-Meier method, including median, quartile and 95% confidence interval
Time frame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual
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Overall survival (OS)
defined as the time from receiving the first study drug treatment to the subject's death, estimated by the Kaplan-Meier method, including median, quartile and 95% confidence interval;
Time frame: From baseline until the reported death of the patients due to any causes, up to 3 years after accrual
Quality of life assessed by patient-reported outcomes (PROs)
The quality of life score using PROs based on EORTC QLQ-C30 scale (adult) or Paediatric Quality of Life Inventory (PedsQL) scale at baseline and at each followed up after treatment.
Time frame: From baseline until the reported death of the patients due to any causes, up to 3 years after accrual
Number of participants with adverse events
Number of participants with Treatment emergent adverse events (TEAE) and serious adverse events (SAE). AE was defines as any toxicities in a participant who received study therapy irrespective of the causal relationship. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity or inpatient hospitalization or prolongation of existing hospitalization.
Time frame: From the first dose of study treatment to 30 days after the last dose of study treatment or before the start day of new anti-cancer drug therapy, whichever occurs first, up to 3 years.