Phase II Randomized Study of Atezolizumab with SBRT Versus SBRT Alone in Oligometastatic Soft Tissue Sarcoma Patients

Trial ID: 2024-511313-38-00
Protocol: 2017-004239-35
Sponsor: Centre Antoine Lacassagne

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Diseases & Conditions

Soft tissue sarcoma

Objectives

The primary objective of this study is to evaluate the efficacy of **immunomodulated stereotactic irradiation** in patients with oligometastatic **soft tissue sarcoma**, specifically by assessing the progression-free survival (PFS) rate at 6 months. This is clinically relevant as it aims to determine the potential benefits of combining high-dose radiation with immunotherapy, which could lead to improved management and outcomes for patients with this condition.

Secondary objectives include:

PFS by immune response criteria.
Ratio of PFS after radiotherapy to PFS during the previous line of treatment.
Objective response rate.
Rate of 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 patients treated with the combination of radio- and immunotherapy or radiotherapy only.
Evaluation of the cost of treatment.
Rate of PET-CT at inclusion.
Impact of biomarkers on PFS.
Impact of biomarkers on response rate.
Developing mathematical models of tumor growth and dissemination for STS treatment by SBRT + immunotherapy predictive of oligo versus poly metastatic evolution.

Participants

The clinical trial involves participants diagnosed with **Soft Tissue Sarcoma**, specifically targeting those with oligometastatic sarcoma. The study population includes both male and female subjects aged 18 years and older, with a performance status of 0 or 1 on the ECOG Performance Scale, indicating they are in relatively good health. Participants must demonstrate adequate organ function and have progressive metastatic disease, with 1-5 synchronous macroscopic metastases. The trial does not focus on a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include histologically confirmed sarcomas, and participants must have at least one measurable lesion suitable for irradiation. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Key inclusion criteria emphasize the need for participants to be willing and able to provide informed consent and to be affiliated with a health insurance system. The trial does not specify any exclusion criteria related to lifestyle habits such as smoking or alcohol consumption.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **atezolizumab** in combination with high-dose radiation therapy compared to radiation therapy alone in patients with oligometastatic **soft tissue sarcoma**. The primary objective is to assess the progression-free survival (PFS) rate at six months. The trial is expected to run until February 3, 2031, with recruitment having commenced on August 4, 2020. Participants will be randomly assigned to one of two treatment arms, receiving either the combination therapy or radiation therapy alone. The study involves intravenous administration of Tecentriq 1200 mg concentrate for solution for infusion, with a maximum treatment period of 105 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven soft tissue sarcoma, adequate organ function, and a performance status of 0 or 1 on the ECOG Performance Scale. Follow-up visits will be scheduled to monitor treatment response, assess safety, and evaluate secondary endpoints, including overall survival and quality of life. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 105 days, depending on individual response and treatment tolerance.

Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will also evaluate secondary endpoints such as objective response rate, toxicity, and the impact of biomarkers on PFS. The study aims to provide valuable insights into the potential benefits of combining immunotherapy with radiation in treating oligometastatic soft tissue sarcomas.

Treatment

The clinical trial involves the administration of **Tecentriq**, a concentrate for solution for infusion, containing the active substance **atezolizumab**. Atezolizumab is a monoclonal antibody classified under the ATC code L01FF05, and it is derived from a protein of other origin. The pharmaceutical form of Tecentriq is a solution for infusion, and it is administered via **intravenous administration**. The dosage regimen for this trial specifies a maximum daily dose of 1200 mg, with a total maximum dose of 7200 mg over the course of the treatment period. The maximum treatment period is set at 105 days. Tecentriq is not a pediatric formulation and is not classified as an orphan drug. The product is authorized for use in the European Union under the marketing authorization number EU/1/17/1220/001, and it is manufactured by Roche Registration GmbH.

In this randomized Phase II, 2-arm study, the experimental treatment involves the use of atezolizumab in conjunction with high-dose radiation therapy, specifically stereotactic body radiation therapy (SBRT), in patients with oligometastatic sarcomas. The primary objective of the trial is to evaluate the efficacy of this immunomodulated stereotactic irradiation approach in terms of progression-free survival rate at 6 months. The study design includes a comparator arm where patients receive SBRT alone, serving as the standard-of-care therapy. Participant compliance with the dosing schedule and administration protocol is monitored throughout the trial to ensure adherence to the treatment regimen.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the **progression-free survival (PFS)** rate at 6 months. This primary endpoint will evaluate the effectiveness of immunomodulated stereotactic irradiation in patients with oligometastatic sarcomas. Secondary endpoints include PFS by immune response criteria, objective response rate according to RECIST criteria version 1.1, and overall survival. The trial will also assess the rate of PFS at 6 months by line of treatment and histology, as well as toxicity evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0, focusing on grades ≥ 3.

Quality of life will be measured using the standard EORTC QLQ-C30 questionnaire. The impact of biomarkers, including PD1/PDL1 immunostaining in tumor and microenvironment, CRP, albumin, neutrophils/lymphocytes, mutational load at baseline, and ctDNA analyses at baseline, 6 months, and relapse, will be analyzed for their effect on PFS. The trial will also validate predictive models and calculate the cost of treatment based on the length of hospitalization. Efficacy assessments will be conducted at specified timepoints, including baseline, 6 months, and at relapse, using validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically proven STS (uterine/extra-uterine leiomyosarcomas, liposarcomas, undifferentiated sarcomas), any grade. A diagnosis confirmation by the RREPS network is preferable but not mandatory.
Progressive disease according to RECIST 1.1 criteria
Metastatic disease (1-5 synchronous macroscopic metastases by chest and abdominopelvic CT, maximal cumulated diameter 10 cm); any anatomic site
Have at least one measurable lesion according to RECIST 1.1 criteria for irradiation with a size < 5 cm,
First or second metastatic line
Be ≥ 18 years of age on day of signing informed consent
Have a performance status of 0 or 1 on the ECOG Performance Scale
Demonstrate adequate organ function: - Absolute neutrophil count (ANC) ≥1,500 /mcL; - Platelets ≥100,000 / mcL; Hemoglobin ≥9 g/dL or ≥5.6 mmol/L; - Serum creatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance with MDRD equation (GFR can also be used in place of creatinine or CrCl) ≥50 mL/min for subject with creatinine levels > 1.5 X institutional ULN; - Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN; - AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases.
Surgical ablation (or other ablative methods such as thermal ablative methods) remains possible if needed before SBRT, at least 4 weeks before randomization and provided that at least one lesion needs to be treated by SBRT,
Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy,
Patient willing and able to provide written informed consent/assent for the trial,
Patient affiliated with a health insurance system,

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Exclusion Criteria

Is currently participating in, or has participated in, a study of an investigational agent or using an investigational device within 4 weeks prior to randomization
Has had prior chemotherapy or targeted small molecule therapy within 4 weeks prior to randomization or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent (Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study). If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy,
Have had previous radical radiation to any tumor site within 4 weeks prior to randomization
Have had previous ablative treatment within 4 weeks prior to randomization (radiofrequency, surgery),
Has had major surgery or major blood transfusions (>3 packed cells) in the past 3 months prior randomization,
Has had a prior monoclonal antibody within 4 weeks prior to randomization or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier,
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways),
Receives IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses),
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment,
Has an active autoimmune disease requiring systemic treatment within the past 3 months prior randomization or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the study,
Has evidence of symptomatic interstitial lung disease or an active, non-infectious pneumonitis,
Has an active infection requiring systemic therapy,
Has received a live vaccine within 30 days prior to the first dose of trial treatment,
Has a tumor within 5 mm of the spinal cord (owing to rare reported cases of flare-up after initiation of immunotherapy),
Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy,
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),
Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA [qualitative] is detected),
Has known Hypersensitivity to Atezolizumab or to any of the excipients (L-histidine, Glacial acetic acid,Sucrose,Polysorbate 20),
Has known liver disease that could increase susceptibility to or exacerbate the impact of any potential hepatotoxicity of Atezolizumab,
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator,
Has known psychiatric or substance-abuse disorders that would interfere with cooperation with the requirements of the trial,
Is pregnant or breastfeeding or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment,
Is a vulnerable persons as defined by article L1121-5 - 8: 1/Pregnant women, women in labour or breast-feeding mothers, persons deprived of their freedom by judicial or administrative decision, persons hospitalized without their consent by virtue of articles L. 3212-1 and L. 3213-1 and who are not subject to the provisions of article L. 1121-8. 2/Persons admitted to a social or health facility for reasons other than research. 3/ Adults subject to a legal protection order or unable to give their consent