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Sarcoma

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Soft Tissue Sarcoma

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Fluzoparib

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Bone tumor subgroup (bone arm) includes high-grade osteosarcoma, chondrosarcoma, undifferentiated bone sarcoma and other rare bone sarcomas with complex genomic features..

Soft tissue sarcoma subgroup (soft tissue arm) includes leiomyosarcoma, pleomorphic rhabdomyosarcoma, angiosarcoma, fibrosarcoma, epithelioid sarcoma, malignant peripheral nerve sheath tumor(MPNST) and other rare soft tissue sarcomas with complex genomic features.

Immune hot tumor subgroup (UPS/DDLPS arm) includes undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS).

Patients receive Camrelizumab (PD-1 inhibitor) and fluzoparib (PARP inhibitor) with concurrent stereotactic body radiotherapy (SBRT)

Camrelizumab and fluzoparib with concurrent stereotactic body radiotherapy (SBRT)

Weibin Zhang, PhD, MD

Yuhui Shen, PhD, MD

Qiyuan Bao, MD., Ph.D

Qiyuan Bao, PhD, MD

Junxiang Wen, PhD, MD

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.

PARP Inhibition, Stereotactic Body Radiotherapy and Immunotherapy for Metastatic or Advanced Sarcoma (PRIMA)

A Prospective Phase II Study of PARP Inhibition and Check Point-inhibition Immunotherapy With Concurrent Stereotactic Body Radiotherapy (SBRT) in Patients With Metastatic or Advanced Sarcoma

individual participant data (IPD) will be available to academic research upon reasonable request, under the local offical rules and regulations.

The PFS for each subgroups in terms of clinicopathological and genomic characteristics (age, gender, histological type, solitary or multiple metastases, unilateral or bilateral metastases, early or late metastases, calcifying or non-calcifying lesions, with or without lesion cavitation, with or without AEs, etc.

The correlative relationship between the tumor response and the genomic biomarker (i.e.

homologous recombination-related \[HRR\] gene mutation, homologous recombination deficiency (HRD) score (LOH+TAI+LST), and RAD51 functional testing) and the therapeutic outcome.

Tumor microenvironment change (immune infiltration, PD-1/PD-L1 expression, immunogenic death, etc.) pre- and post- SBRT, and conduct correlative analysis between these immune microenvironment indeces and the therapeutic outcome.

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.

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

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;

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

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

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;

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PARP Inhibition, Stereotactic Body Radiotherapy and Immunotherapy for Metastatic or Advanced Sarcoma (PRIMA)	NCT06074692	Sarcoma Sarcoma,Soft Ti... Sarcoma of Bone	Camrelizumab an...	10 Years - 70 Years	Ruijin Hospital
PARP Inhibition, Stereotactic Body Radiotherapy and Immunotherapy for Metastatic or Advanced Sarcoma (PRIMA)	NCT06074692	Sarcoma Sarcoma,Soft Ti... Sarcoma of Bone	Camrelizumab an...	10 Years - 70 Years	Ruijin Hospital

Spots Global Cancer Trial Database for camrelizumab and fluzoparib with concurrent stereotactic body radiotherapy (sbrt)