Stereotaxic Body Irradiation of Oligometastase in Sarcoma (Stereosarc) (Stereosarc)
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|ClinicalTrials.gov Identifier: NCT03548428|
Recruitment Status : Not yet recruiting
First Posted : June 7, 2018
Last Update Posted : March 18, 2019
Up to 50% of soft tissue sarcoma (STS) patients will develop metastases in the course of their disease. Cytotoxic therapy is a standard treatment in this setting but yields average tumor response rates of 25% at first line and ≤10% at later lines. It is also limited in the number of lines and courses by tolerance issues. Trials include poly/oligometastases indistinctively and suggest that consolidation ablation is used in ~20% of patients with residual oligometastases refractory to chemotherapy. Oligometastases represent a stage of disease between completely absent and widely metastatic, and which might be cured if the limited numbers of metastatic sites are eradicated. Ablative strategies to treat patients with oligometastases from sarcomas yield prolonged survival times and stereotactic body radiation therapy (SBRT) is associated with excellent tolerance. Surgery may be offered in selected metastatic cases. Alternatively and increasingly, SBRT yields high control rates at treated sites (≥ 80%). The so-called radioresistance of sarcomas is overcome by the high doses per fraction made possible owing to the high precision achieved with SBRT. SBRT is an accepted treatment strategy provided that tumor burden remains limited in the number and size of metastases. Systemic treatment can be combined with SBRT. SBRT may produce abscopal effects where tumors outside the irradiation area also demonstrate tumor shrinkage in some occurrences. SBRT produces systemic antitumoral immune response in certain conditions and enhances radiation-induced tumor cell death compared to conventional lower dose irradiation. Abscopal effects have been potentialized with SBRT/immunotherapy in several tumor models. Sarcomas are a privileged target tumor given their high metastatic propensity.
Several potent immunomodulators that skew the tumor immune microenvironment toward a proimmunity context are being investigated in STS either alone or in combination with chemotherapy or targeted therapy. The PD-1 receptor is present within the tumor microenvironment, and limits the activity of infiltrating cytotoxic T lymphocytes, thus blocking effective immune responses. The action of PD-1 is triggered upon binding to its ligands. PD-1 can stimulate the immunosuppressive function of regulatory T cells. Moreover, blockade of PD-1 can stimulate anti-tumor immune responses. Significant responses have been obtained in several sarcomas with acceptable tolerance. Preliminary clinical experience suggests that immunotherapy can be efficient in refractory leiomyosarcomas. Several drugs targeting the PD-1/PD-L1/2 axis are ongoing either as single agents or in combination with ipilimumab, kinase inhibitors, or chemotherapy in STS subtypes. Combination of radiotherapy with immunotherapy is included as a means of increasing tumor antigen release in metastatic STS. Immunomodulated SBRT is a particularly attractive strategy, given the potential of radiation to induce cytotoxicity in tumors and induce abscopal effects. A phase II radiation trial showed increased apoptosis-, intra-tumoral dendritic cells and accumulation of intratumoral T cells in STS with correlation with tumor-specific immune responses.
We here propose a randomized phase II study to prolong progression-free survival (PFS) with the combination of SBRT/immunotherapy in oligometastatic STS patients.
SBRT is well-tolerated with hardly any severe toxicity (fewer than 5% acute and late grade 3 toxicities). It is performed in an ambulatory setting in only a few treatment fractions. Associations between irradiation and immunomodulatory agents appear to be synergistic and show favorable tolerance profiles. Immunomodulatory agents have a more favorable toxicity profile than cytotoxic agents with about 65% overall acute toxicities. Immunotherapy selectively binds to PD-L1 and competitively blocks its interaction with PD-1.
Compared with anti-PD-1 antibodies that target T-cells, immunotherapy targets tumor cells, and is therefore may induce fewer side effects, including a lower risk of autoimmune-related safety issues, as blockade of PD-L1 leaves the PD-L2 - PD-1 pathway intact to promote peripheral self-tolerance.
Stereotactic irradiation is associated with an excellent tolerance with rates of grade 3 or more toxicities below 5%.
Preliminary data of toxicity with the association of stereotactic irradiation and immunotherapy show no cumulative toxicity in association with immunotherapy. However, their incidence and characteristics are no different from that observed with stereotactic irradiation alone. Moreover, intracranial metastases are exceptional in sarcomas.
The toxicity of the association for extracranial stereotactic irradiation does not seem to be increased either.
|Condition or disease||Intervention/treatment||Phase|
|Sarcoma Radiosurgery||Drug: Atezolizumab Radiation: SBRT||Phase 2|
Open label, Phase II, prospective, multicentric, randomized study 2:1, 2 arm study designed to evaluate the efficacy of a Stereotactic Body Radiation Therapy treatment associated with immunotherapy versus a Stereotactic Body Radiation Therapy treatment only.
Primary objective The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic irradiation in oligometastatic sarcoma patients.
- PFS by immune response criteria.
- ratio PFS after radiotherapy/PFS during the previous line of treatment
- Objective response rate.
- Rate of progression-free survival (PFS) at 6 months by line of treatment and histology.
- Evaluation of the toxicity of the treatment.
- Overall survival.
- Evaluation of the quality of life of patient treated by the combination of radio- and immunotherapy or radiotherapy only.
- Evaluation of the cost of treatment.
- Rate of PET-CT at inclusion
- Correlative study: Impact of biomarkers on clinical endpoints.
- Developing a mathematical models for STS treatment by SBRT + immunotherapy predictive of oligo versus poly metastatic evolution
The treatment to be used in this study is the Atezolizumab concomitant with High Dose Radiation (SBRT) or the SBRT Alone Atezolizumab Subjects randomized in the experimental arm will receive Atezolizumab 1200 mg in combination with SBRT, Q3W (6 cycles) for 4 months until progression/completion. The Atezolizumab will be provided by the Sponsor (Centre Antoine Lacassagne).
Chemotherapy will be discontinued in case of progression, unacceptable toxicity, or withdrawal of patient consent to receive study treatment.
Radiation therapy SBRT can be performed with different equipments (CyberKnife, Truebeam, etc.). Adequate tumor tracking and patient setup/repositioning as well as online IGRT (image-guided radiation therapy) must be performed at each fraction. The maximal cumulative tumor diameter is 6 cm to maintain an advantageous risk-benefit ratio with SBRT. Two types of fractionation are proposed to account for tumor size and proximity of the tumor to sensitive organs at risk. Three fractions are proposed in favorable cases, 5 in more delicate cases. Fractions can be performed on consecutive days. Depending on cases, they may be delivered every other day; the whole SBRT duration should not exceed 3 weeks.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||103 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Open label, Phase II, prospective, multicentric, randomized study 2:1, 2 arm study|
|Masking:||None (Open Label)|
|Official Title:||Randomized Phase II, 2-arm Study of Immunomodulation With Atezolizumab Concomitant With High Dose Radiation (SBRT) Versus SBRT Alone in Patients With Oligometastatic Sarcomas|
|Estimated Study Start Date :||September 1, 2019|
|Estimated Primary Completion Date :||August 1, 2021|
|Estimated Study Completion Date :||August 1, 2026|
SBRT + Atezolizumab
1200mg IV every 3 weeks for 4 months
3 to 5 fractions depending on tumor size
Other Name: High Dose Radiation
Active Comparator: B
3 to 5 fractions depending on tumor size
Other Name: High Dose Radiation
- efficacy, in term of progression-free survival (PFS) rate at 6 months [ Time Frame: 6 months ]Rate of progression-free survival (PFS)
- PFS by immune response criteria. [ Time Frame: 5 years ]PFS by immune response criteria defined as the time between the date of randomizationrandomisation and the date of progression or the date of death or the date of last news.
- ratio PFS after radiotherapy/PFS during the previous line of treatment [ Time Frame: 5 years ]ratio PFS after radiotherapy/PFS during the previous line of treatment
- Objective response rate. [ Time Frame: 5 years ]Objective response rate defined according to RECIST criteria version 1.1
- Rate of progression-free survival (PFS) at 6 months by line of treatment and histology. [ Time Frame: 6 months ]Rate of progression-free survival (PFS) at 6 months as defined in the primary endpoint by line of treatment and by histology
- Evaluation of the toxicity of the treatment [ Time Frame: 6 months ]Toxicity will be graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. The rate of grade ≥ 3 toxicities will be evaluated.
- Overall survival [ Time Frame: 5 years ]Overall Survival defined as the time between the date of randomizationrandomisation and the date of death or the date of last news for those still alive at the end of the follow-up.
- Evaluation of the quality of life of patient treated by the combination of radio- and immunotherapy or radiotherapy only [ Time Frame: 2 years ]Quality of life will be measured using standard quality of life questionnaire EORTC QLQc30
- Evaluation of the cost of treatment [ Time Frame: 4 months ]The cost of the treatment will be calculated on the basis of the length of hospitalization in days
- Rate of PET-CT at inclusion [ Time Frame: Baseline ]Rate of PET-CT scan performed at inclusion
- Impact of biomarkers on PFS. [ Time Frame: baseline, 6 months, at relapse within 5 years ]Impact of biomarkers (PD1/PDL1 immunostaining in tumor and microenvironment, CRP, albumin, neutrophils/lymphocytes at baseline and ctDNA at baseline, 6 months and relapse) on pfs
- Impact of biomarker on response rate. [ Time Frame: baseline, 6 months, at relapse within 5 years ]Impact of biomarkers (PD1/PDL1 immunostaining in tumor and microenvironment, CRP, albumin, neutrophils/lymphocytes at baseline and ctDNA at baseline, 6 months and relapse) on response rate
- Developing a mathematical models for STS treatment by SBRT + immunotherapy predictive of oligo versus poly metastatic evolution [ Time Frame: 5 years ]Validation of the predictive models
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03548428
|Contact: Colin DEBAIGT, PhD||0033 4 92 03 17 78||DRCI-Promotion@nice.unicancer.fr|
|Principal Investigator:||Juliette THARIAT, MD||Centre Hospitalier Universitaire de Caen|