A Phase 2 interventional study of metastasectomy and pre-operative immunotherapy (gemcitabine and penpulimab ) and stereotactic body radiotherapy in Osteosarcoma, sponsored by Ruijin Hospital. Recruiting at 1 site in China. Open to participants aged 10 Years to 65 Years. Per ClinicalTrials.gov, last updated 2023-11-02.
Sponsored by Ruijin Hospital · Phase 2, Interventional, and Treatment
The aim of this study is to evaluate the efficacy and safety of pre-operative concurrent Stereotactic Body Radiotherapy (SBRT) and and programmed cell death protein-1 (PD-1) blockade immunotherapy followed by surgical metastasectomy for resectable metastatic osteosarcoma.
Osteosarcoma is a primary bone malignant tumor with strong metastatic potential. About 15%-20% of osteosarcomas are accompanied by lung metastasis when diagnosed, and about 40% of patients develop secondary lung metastasis after radical surgery of the primary lesion. However, pulmonary metastatic osteosarcoma are often insensitive to traditional radiotherapy and chemotherapy. For resectable lung metastases, the preferred treatment is still complete resection of all metastases and the best therapeutic modality and regimens pre- and post-surgical remains unestablished.
With the advent of immunotherapy, many common solid tumors have made substantial progress through immunotherapy after distant metastasis. However, a number of current clinical studies on immunotherapy for osteosarcoma have shown that the effective rate of immunotherapy for osteosarcoma is about 5% to 10% after single agent treatment, making it regarded as one of the "immune cold" tumor, potentially due to the fact that osteosarcoma often lacks immune cell infiltration, and immune cells in tumors are often difficult to be activated or preserve immune memory. However, the investigators have found in our previous clinical observations that a small number of osteosarcoma patients not only have significant effects on immunotherapy, but even have long-term responses. The investigators unexpectedly found that the degree of tumor pro-inflammatory factors and lymphocyte infiltration in the osteosarcoma sample significantly increased after radiotherapy, especially SBRT. The investigators also discovered that the induction of the formation of "tertiary lymphatic structure" within the tumor might be possible through SBRT as a potential sensitization strategy for immunotherapy in osteosarcoma, which is consistent with the recent knowledge of rado-immunotherapy of several solid tumors.
Therefore, the investigators aim to conduct a prospective phase II clinical trial on pre-operative immunotherapy and stereotactic body radiotherapy (SBRT), followed by metastasectomy in patients with pulmonary resectable recurrence of osteosarcoma. To explore the potential mechanisms related to the pre-operative sensitization of immunotherapy, correlative biomarker analysis is to be performed to explore the tumor microenvironment pre- and post- SBRT to pave the way for further precision immunotherapy of bone sarcoma in the future.
437 studies on the registry are indexed under Osteosarcoma; 116 are open to participants now.
This study's planned enrollment of 43 is close to the median of 42 across 325 interventional studies indexed under Osteosarcoma.
Browse Osteosarcoma studies →Ruijin Hospital is the lead sponsor of 635 studies on the registry; 359 are open to participants now.
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If there are recurrent lesions previously treated by surgery, radiofrequency ablation or radiotherapy:
Exclusion Criteria:
The participant receive metastasectomy, immunotherapy and Stereotactic Body Radiotherapy (SBRT)
Combination Product: metastasectomy and pre-operative immunotherapy (gemcitabine and penpulimab ) and stereotactic body radiotherapy
participants first receive concurrent SBRT and penpulimab (PD-1 blockade) and two cycles of GP regimen (gemcitabine d1,d8 and Penpulimab d8 per a 21-day cycle), followed by complete pulmonary metastasectomy. After surgery, participant receive another 4 cycles of GP regimens followed by Penpulimab monotherapy maintenance. The rationale is that pre-operative SBRT could boost the immune microenvironment, leading to a long-term effect of immunotherapy post-metastasectomy and eventually resulting in better long-term survivorship compared to the histological control for pulmonary resectable recurrence of osteosarcoma .
12-month progression-free survival rate (12m-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: 12 months from recruitment
Objective response 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, death or the time of metastasectomy, whichever occurs first, up to 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, death or the time of metastasectomy, 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
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)
Assessement of 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.
The rate of tumor resectability
Tumor resectability is defined as the number of patients undergoing pre-planned metastasectomy divided by the number of patients considered resectable at baseline.
Time frame: At the time of metastasectomy, an average of 8~9 weeks
The incidence of peri-operative complications
Peri-operative complications is defined as the incidence of complications during and following metastasectomy surgery
Time frame: At the time of metastasectomy, an average of 8~9 weeks
Exploratory outcome: progression-free survival(PFS) in different subgroups
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.
Time frame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual.
Exploratory outcome: the molecular analysis of tumor sample in correlation with the oncological outcome
To explore the molecular correlative relationship between the genomic complexity(i.e. TMB, neoantigen burden, genomic instability) and the therapeutic outcome.
Time frame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual.
Exploratory outcome: the expression of immune infiltration biomarker of tumor sample in correlation with the oncological outcome.
To explore the tumor microenvironment (immune infiltration, PD-1/PD-L1 expression, immunogenic death, etc.) pre- and post- SBRT, and conduct correlative analysis between these immune microenvironment indexes and the therapeutic outcome.
Time frame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual.
Plan to share: Undecided — individual participant data (IPD) will be available to academic research upon reasonable request, under the local official rules and regulations.
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