Randomized Phase II, 2-arm Study of Immunomodulation with Atezolizumab concomitant with High Dose Radiation (SBRT) Versus SBRT Alone in Patients with Oligometastatic Sarcomas

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Antoine Lacassagne

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Nov 2024 → ongoing

Decision date (initial)

2024-11-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-511313-38-00

EudraCT number

2017-004239-35

ClinicalTrials.gov

NCT03548428

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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.

Secondary objectives 12

1. PFS by immune response criteria
2. Ratio PFS after radiotherapy/PFS during the previous line of treatment.
3. Objective response rate.
4. Rate of progression-free survival (PFS) at 6 months by line of treatment and histology.
5. Evaluation of the toxicity of the treatment.
6. Overall survival.
7. Evaluation of the quality of life of patient treated by the combination of radio- and immunotherapy or radiotherapy only.
8. Evaluation of the cost of treatment.
9. Rate of PET-CT at inclusion.
10. Impact of biomarkers on PFS.
11. Impact of biomarker on response rate.
12. Developing mathematical models of tumor growth and dissemination for STS treatment by SBRT + immunotherapy predictive of oligo versus poly metastatic evolution.

Conditions and MedDRA coding

Soft Tissue Sarcoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Histologically proven STS (uterine/extra-uterine leiomyosarcomas, liposarcomas, undifferentiated sarcomas), any grade. A diagnosis confirmation by the RREPS network is preferable but not mandatory.
2. Progressive disease according to RECIST 1.1 criteria
3. Metastatic disease (1-5 synchronous macroscopic metastases by chest and abdominopelvic CT, maximal cumulated diameter 10 cm); any anatomic site
4. Have at least one measurable lesion according to RECIST 1.1 criteria for irradiation with a size < 5 cm,
5. First or second metastatic line
6. Be ≥ 18 years of age on day of signing informed consent
7. Have a performance status of 0 or 1 on the ECOG Performance Scale
8. 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.
9. 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,
10. 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,
11. Patient willing and able to provide written informed consent/assent for the trial,
12. Patient affiliated with a health insurance system,

Exclusion criteria 23

1. 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
2. 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,
3. Have had previous radical radiation to any tumor site within 4 weeks prior to randomization
4. Have had previous ablative treatment within 4 weeks prior to randomization (radiofrequency, surgery),
5. Has had major surgery or major blood transfusions (>3 packed cells) in the past 3 months prior randomization,
6. 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,
7. 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),
8. 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),
9. 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,
10. 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,
11. Has evidence of symptomatic interstitial lung disease or an active, non-infectious pneumonitis,
12. Has an active infection requiring systemic therapy,
13. Has received a live vaccine within 30 days prior to the first dose of trial treatment,
14. Has a tumor within 5 mm of the spinal cord (owing to rare reported cases of flare-up after initiation of immunotherapy),
15. 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,
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),
17. Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA [qualitative] is detected),
18. Has known Hypersensitivity to Atezolizumab or to any of the excipients (L-histidine, Glacial acetic acid,Sucrose,Polysorbate 20),
19. Has known liver disease that could increase susceptibility to or exacerbate the impact of any potential hepatotoxicity of Atezolizumab,
20. 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,
21. Has known psychiatric or substance-abuse disorders that would interfere with cooperation with the requirements of the trial,
22. 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,
23. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The rate of progression-free survival (PFS) at 6 months.

Secondary endpoints 10

1. PFS by immune response criteria defined as the time between the date of D1 of treatment and the date of progression or the date of death or the date of last news
2. Objective response rate defined according to RECIST criteria version 1.1
3. Rate of progression-free survival (PFS) at 6 months as defined in the primary endpoint by line of treatment and by histology
4. Toxicity will be evaluated according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0. Toxicities of all grades will be analyzed and then the analysis will be focused on grades ≥ 3
5. Overall Survival defined as the time between the date of D1 of treatment and the date of death or the date of last news for those still alive at the end of the follow-up
6. Quality of life will be measured using standard EORTC QLQc30
7. The cost of the treatment will be calculated on the basis of the length of hospitalization in days.
8. Rate of PET-CT scan performed at inclusion.
9. 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) on PFS as previously described
10. Validation of the predictive models.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Antoine Lacassagne

Sponsor organisation

Centre Antoine Lacassagne

Address

33 Avenue De Valombrose

City

Nice Cedex 2

Postcode

06189

Country

France

Scientific contact point

Organisation

Centre Antoine Lacassagne

Contact name

Dr Esma Bouzid Saada

Public contact point

Organisation

Centre Antoine Lacassagne

Contact name

Dr Esma Bouzid Saada

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications