Clinical trial NCT06074692: PARP Inhibition, Stereotactic Body Radiotherapy and Immunotherapy for Metastatic or Advanced Sarcoma (PRIMA)
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Sarcoma
Sarcoma,Soft Tissue
Sarcoma of Bone
Keywords: sarcoma
bone and soft tissue sarcoma
PARP inhibitor
SBRT
checkpoint inhibitor
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
First posted: 2023-10-10
Enrollment: 86
Sex: ALL
Minimum age (years): 10
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent signed before any trial-related procedures are carried out
2. Histologically confirmed high-grade sarcoma of bone or soft tissue; the lesion has distant metastasis or is locally advanced and cannot be completely resected at the time of enrollment, or the patient cannot tolerate or refuses surgical resection;
3. Have received at least one systemic treatment regimen(s) at the time of enrollment, and have not received prior PARP inhibitor treatment.
4. With measurable lesions according to Response Evaluation Criteria in Solid Tumors (RECIST1.1);
5. Aged no less than 10 years old and no more than 70 years old;
6. For patients ≥16 years old, ECOG score is between 0 and 2 (for patients with amputations, if they can basically take care of themselves and can move freely for more than 50% of their waking hours with the assistance of stretchers, walkers, wheelchairs, etc.) still included);
7. For patients under 16 years old, Lansky score is at least 70 or above (for patients with amputations who are unable to participate in active recreational activities due to amputation), if they can participate in most active recreational activities with the assistance of walkers, wheelchairs, etc., they are still eligible included).
8. The expected survival time is greater than 24 weeks;
9. The majority of the recurrent lesions with an established radiological diagnosis could receive SBRT;
10. Major organ functions meet basic safety standards within 7-14 days before treatment.
11. Women of childbearing age should agree that they must use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; if in doubt, serum or urine tests within 7 days before study enrollment The pregnancy test is negative and the patient must be non-lactating; the male should agree that contraceptive measures must be used during the study period and within 6 months after the end of the study period;
12. If there are recurrent lesions previously treated by surgery, radiofrequency ablation or radiotherapy:

    1. If the image of the metastatic lesion is stable, enrollment is allowed and SBRT is not required for that lesion;
    2. If the metastatic lesion has image progression, if it was previously treated with surgery and SBRT can be performed, enrollment is allowed; if it was previously treated with radiofrequency ablation or radiotherapy, if repeat SBRT can be considered, enrollment is allowed.

Exclusion Criteria:

1. Diagnosed with malignant diseases other than tumors within 5 years before the first dose;
2. Currently participating in interventional clinical research treatment, or have received other research drugs or used research equipment within 4 weeks before the first dose;
3. Previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs or drugs targeting another stimulating or synergistic inhibition of T cell receptors (e.g., CTLA-4, OX-40, CD137) drug and secondary resistance to the drug (i.e., the best efficacy evaluation is CR, PR or SD lasting more than 4 months, but secondary tumor resistance develops after treatment).
4. Received systemic systemic treatment with Chinese patent medicines with anti-tumor indications or drugs with immunomodulatory effects (including thymosin, interferon, interleukin, except local use to control pleural effusion) within 2 weeks before the first dose;
5. Active autoimmune disease requiring systemic treatment (such as use of disease-modifying drugs, glucocorticoids, or immunosuppressants) within 2 years before the first dose. Replacement therapies (such as thyroxine, insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency, etc.) are not considered systemic treatments;
6. Are receiving systemic glucocorticoid treatment (excluding nasal spray, inhaled or other route of topical glucocorticoids) or any other form of immunosuppressive therapy within 7 days before the first dose of the study;
7. Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
8. Known to be allergic to any components of monoclonal antibody preparations (have experienced grade 3 or above allergic reactions);
9. Have not fully recovered from toxicity and/or complications caused by any intervention before initiating treatment (i.e., ≤Grade 1 or reaching baseline, excluding fatigue or alopecia);
10. Known history of human immunodeficiency virus (HIV) infection (i.e. HIV1/2 antibody positive);
11. Get live vaccine within 30 days before the first dose (cycle 1, day 1);
12. Pregnant or lactating women;
13. Any serious or uncontrollable systemic disease

Primary outcomes:
measure: 6-momth progression-free survival rate (6m-PFSR)
timeFrame: 6 months from recruitment
Secondary outcomes:
measure: Objective respones rate (ORR)
timeFrame: From baseline to disease progression or death, whichever occurs first, until 3 years after accrual
measure: Disease control rate (DCR)
timeFrame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual
measure: Duration of response (DOR)
timeFrame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual
measure: Progression-free survival (PFS)
timeFrame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual
measure: Overall survival (OS)
timeFrame: From baseline until the reported death of the patients due to any causes, up to 3 years after accrual
measure: Quality of life assessed by patient-reported outcomes (PROs)
timeFrame: From baseline until the reported death of the patients due to any causes, up to 3 years after accrual
measure: Number of participants with adverse events
timeFrame: 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.
Other outcomes:
measure: Exploratory outcome: progression-free survival(PFS) in different subgroup
timeFrame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual.
measure: Exploratory outcome: the homologous recombination deficiency (HRD) score in tumor samples
timeFrame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual
measure: Exploratory outcome: the expression of immune infiltration biomarker in tumor samples
timeFrame: From baseline to disease progression or death, whichever occurs first, up to 3 years after accrual.
Locations:
city: Shanghai
country: China
facility: Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine
state: Shanghai
Study officials:
affiliation: Ruijin Hospital
name: Weibin Zhang, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ruijin Hospital
name: Yuhui Shen, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ruijin Hospital
name: Qiyuan Bao, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ruijin Hospital
name: Junxiang Wen, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References: