Overview

This study (phase I clinical trial and expansion cohorts) will evaluate safety and efficacy of combination of atezolizumab and tiragolumab, with concomitant or sequential SBRT for four oligometastatic cancer cohorts. This study will allow to developpe one or several randomized Phase II clinical trials for the more promising indications

Eligibility

Inclusion Criteria:

• Age ≥ 18 years,
• ECOG, Performance status ≤ 1,
• Minimum 3 measurable lesions, with at least one lesion which cannot be irradiated for testing the abscopal effect and at least 2 irradiable lesions.
• Life expectancy > 6 months,
• At least one non irradiated tumor site that can be biopsied for research purpose,
• Participant must have following advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement:

        Cohort 1 : patient with metastatic non small lung cancer / tumor without oncogenic
        addiction (EGFR/ALK/ROS/BRAF) which progress after platin based chemotherapy and
        immunotherapy given as sequential or concomitant therapy.
        Cohort 2 : Bladder cancer / Patient with progression following platin based therapy or
        without maintenance with anti PD1/PD-L1. Patient have to recieve Enfortumab Vedotin before
        inclusion if the treatment is available. Unless indication by the investigator Cohort 3 :
        Renal cell carcinoma / Second-line therapy after an anti-angiogenic plus immunotherapy or
        immunotherapy.
        Cohort 4 : Head and neck carcinoma / First line locoregional or metastatic recurrence
          -  Participants who received prior anti-PD-1/L1 therapy must fulfill the following
             requirements Have achieved a complete response, partial response or stable disease and
             subsequently had disease progression while still on anti-PD-1/L1 therapy Have received
             at least two doses of an approved anti-PD-1/L1 therapy (by any regulatory authority)
          -  Adequate hematological, renal, metabolic and hepatic functions:
        Hemoglobin ≥ 9 g/dl (participants may have received prior red blood cell [RBC] transfusion,
        if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 G/l, platelet count ≥ 100
        G/l, white blood cell count ≥ 2.5 G/l (or within local laboratory normal limits) and
        lymphocyte count ≥ 0.75 G/l Alkaline phosphatase (AP), alanine aminotransferase (ALT) and
        aspartate aminotransferase (ASP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 x ULN in case
        of extensive skeletal involvement for AP exclusively and ≤ 5 x ULN in case of liver
        metastasis for AST and ALT).
        Total bilirubin ≤ 1.5 x ULN, (3 x ULN for gilbert disease) Albumin ≥ 25 g/l. Serum
        creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to
        Cockcroft and Gault formula).
        INR ≤ 1.5 x ULN aPTT ≤ 1.5 X ULN Serum calcium within normal laboratory ranges,
          -  No prior or concurrent malignant disease if more recent than 3 years
          -  At least three weeks since last chemotherapy, immunotherapy or any other
             pharmacological treatment and/or radiotherapy
        Criteria to confirm inclusion:
          -  At least 2 mesurable lesions should be able to receveid 3 X 8 Gy by SBRT according to
             the dose constraints to organs at risk (OAR) imposed by the protocol
          -  In case of lesion previously treated by radiotherapy, the constraints on the organs at
             risk must be respected after having summed up the treatment plans.
          -  Confirmation of 3 measureable lesions, with at least one lesion which cannot be
             irradiated for testing the abscopal effect and at least 2 irradiable lesions. Those
             lesions must be uni-dimensionally ≥ 10 mm considered as measurable according to RECIST
             v1.1
        Exclusion Criteria:
          -  Evidence of symptomatic central nervous system (CNS) or leptomeningeal metastases,
          -  Women who are pregnant or breast feeding,
          -  Participation in a study involving a medical or therapeutic intervention in the last
             30 days from first treatment administration,
          -  Previous enrolment in the present study,
          -  Participant unable to follow and comply with the study procedures because of any
             geographical, familial, social or psychological reasons,
          -  Known hypersensitivity to any involved study drug or of its formulation components,
          -  History of severe allergic anaphylactic reactions to chimeric, human or humanized
             antibodies, or fusion proteins,
          -  Treatment with systemic immunosuppressive medications including, but not limited to,
             cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within
             2 weeks prior to inclusion. Systemic corticosteroids is not allowed but at physiologic
             doses meaning less than 10 mg/day of prednisone or its equivalent. The use of inhaled
             corticosteroids and mineral corticoids is allowed.
          -  Major surgical procedure, open biopsy or significant traumatic injury within 28 days
             before pre inclusion,
          -  Any of the following cardiac criteria:
        Congestive heart failure ≥ New York Heart Association (NYHA) class 2,
          -  Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
             months), Myocardial infarction less than 6 months before pre-inclusion Uncontrolled
             cardiac arrhythmias, Known left ventricular ejection fraction (LVEF) <50%
          -  Individuals deprived of liberty or placed under legal guardianship, curatorship or
             judicial protection.
          -  Prior organ transplantation, including allogeneic stem cell transplantation,
          -  Known clinically significant liver disease, including, alcoholic, or other hepatitis,
             cirrhosis, fatty liver and inherited liver disease, active viral with positive
             viralDNA detection.
          -  History of intra-abdominal inflammatory process within the last 12 months such as, but
             not limited to, diverticulitis, peptic ulcer disease or colitis.
          -  History of autoimmune disease including, but not limited to systemic lupus
             erythematosus (SLE), Sjögren's syndrome, glomerulonephritis, multiple sclerosis,
             rheumatoid arthritis, vasculitis, systemic immune activation, inflammatory bowel
             disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's
             granulomatosis, Guillain-Barré syndrome, Bell's palsy.
        Participants with a history of autoimmune-related hypothyroidism on a stable dose of
        thyroid replacement hormone are eligible, Participants with controlled Type I diabetes
        mellitus on a stable insulin regimen are eligible, Participants with eczema, psoriasis,
        lichen simplex chronicus, or vitiligo with only dermatologic manifestations <10% of the
        skin (e.g., participants with psoriatic arthritis would be excluded) are eligible.
          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan. History of radiation pneumonitis in the
             radiation field (fibrosis) is permitted.
          -  Poorly controlled Type II diabetes mellitus defined as a screening fasting plasma
             glucose ≥160 mg/dL (or 8.8 mmol/L).
          -  Severe infections within 2 weeks prior to inclusion, including but not limited to
             SARS-Cov-2 infection, hospitalization for complications of infection, bacteremia, or
             severe pneumonia.
          -  Received therapeutic oral or IV antibiotics within 2 weeks prior to pre-inclusion.
             Participants receiving prophylactic antibiotics (e.g., for prevention of a urinary
             tract infection or chronic obstructive pulmonary disease) are eligible.
          -  Any contraindication to tumor biopsy,
          -  Participant with spinal cord compression not definitively treated with surgery and/or
             radiation or previously diagnosed and treated spinal cord compression without evidence
             that disease has been clinically stable for >2 weeks prior to pre-inclusion.
          -  Administration of a live, attenuated vaccine within 4 weeks before the start of study
             medication or anticipation that such a live attenuated vaccine will be required during
             the study. Influenza vaccination is allowed during influenza season only
             (approximatively October to March).
          -  Patient with a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies)
             or known acquired immunodeficiency syndrome (AIDS),
          -  Patients with EBV infection (Positive EBV viral capsid antigen IgM test at screening)
          -  Active tuberculosis
          -  Concomitant use of prohibited concomitant therapy (cf paragraph 6.5.2.2) or
             anticipation that such concomitant medication/therapies will be required during the
             study
          -  For NSCLC indication, patients with lymphoepithelioma-like carcinoma are excluded.