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

Last updated: October 29, 2023
Sponsor: Ruijin Hospital
Overall Status: Active - Recruiting

Phase

2

Condition

Sarcoma

Treatment

Camrelizumab and fluzoparib with concurrent stereotactic body radiotherapy (SBRT)

Clinical Study ID

NCT06074692
2023-LLS-220
  • Ages 10-70
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

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 hasdistant metastasis or is locally advanced and cannot be completely resected at thetime 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 withamputations, if they can basically take care of themselves and can move freely formore 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 patientswith amputations who are unable to participate in active recreational activities dueto amputation), if they can participate in most active recreational activities withthe 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 couldreceive 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 (suchas intrauterine devices, birth control pills or condoms) during the study and within 6months after the end of the study; if in doubt, serum or urine tests within 7 daysbefore study enrollment The pregnancy test is negative and the patient must benon-lactating; the male should agree that contraceptive measures must be used duringthe study period and within 6 months after the end of the study period;
  12. If there are recurrent lesions previously treated by surgery, radiofrequency ablationor radiotherapy:
  13. If the image of the metastatic lesion is stable, enrollment is allowed and SBRTis not required for that lesion;
  14. If the metastatic lesion has image progression, if it was previously treated withsurgery and SBRT can be performed, enrollment is allowed; if it was previouslytreated with radiofrequency ablation or radiotherapy, if repeat SBRT can beconsidered, enrollment is allowed.

Exclusion

Exclusion Criteria:

  1. Diagnosed with malignant diseases other than tumors within 5 years before the firstdose;
  2. Currently participating in interventional clinical research treatment, or havereceived other research drugs or used research equipment within 4 weeks before thefirst dose;
  3. Previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2drugs or drugs targeting another stimulating or synergistic inhibition of T cellreceptors (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, butsecondary tumor resistance develops after treatment).
  4. Received systemic systemic treatment with Chinese patent medicines with anti-tumorindications or drugs with immunomodulatory effects (including thymosin, interferon,interleukin, except local use to control pleural effusion) within 2 weeks before thefirst dose;
  5. Active autoimmune disease requiring systemic treatment (such as use ofdisease-modifying drugs, glucocorticoids, or immunosuppressants) within 2 years beforethe first dose. Replacement therapies (such as thyroxine, insulin, or physiologicalglucocorticoids for adrenal or pituitary insufficiency, etc.) are not consideredsystemic treatments;
  6. Are receiving systemic glucocorticoid treatment (excluding nasal spray, inhaled orother route of topical glucocorticoids) or any other form of immunosuppressive therapywithin 7 days before the first dose of the study;
  7. Known allogeneic organ transplantation (except corneal transplantation) or allogeneichematopoietic stem cell transplantation;
  8. Known to be allergic to any components of monoclonal antibody preparations (haveexperienced grade 3 or above allergic reactions);
  9. Have not fully recovered from toxicity and/or complications caused by any interventionbefore initiating treatment (i.e., ≤Grade 1 or reaching baseline, excluding fatigue oralopecia);
  10. Known history of human immunodeficiency virus (HIV) infection (i.e. HIV1/2 antibodypositive);
  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

Study Design

Total Participants: 86
Treatment Group(s): 1
Primary Treatment: Camrelizumab and fluzoparib with concurrent stereotactic body radiotherapy (SBRT)
Phase: 2
Study Start date:
June 01, 2023
Estimated Completion Date:
December 30, 2026

Study 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.

Connect with a study center

  • Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine

    Shanghai, Shanghai 20025
    China

    Active - Recruiting

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