Lymphocyte Support to SBRT in Patients With Oligo-metastatic Solid Cancer

Inclusion Criteria:

• Adult male or female patients (older than 18 years of age at inclusion);

• Histologically or cytologically proven solid cancer at the oligo-metastatic stageamenable to pan-lesion SBRT, as defined by:

1. 2 to 5 tumor lesions measurable as per RECIST V1.1 (including primary) with alargest diameter comprised between 1.5 and 5 cm,

2. The disease can be either genuinely oligo-metastatic, oligo-progressive, or aninduced oligo-metastatic disease,

3. All tumor lesions that match criterion I2a must be eligible to SBRT in terms oflocation and radiotherapy constraints,

4. SBRT to all lesions must be feasible over a two-week period,

5. Whatever the primary tumor type;

• Patients must agree to comply with biopsy and blood sampling for research purpose;

• Minimal wash-out periods from last administration of treatments to the first day ofSBRT must be:

1. Systemic chemotherapy including cytotoxic, immunotherapy, targeted therapy,hormone therapy, any investigational agent during the last 4 weeks,

2. Immunosuppressive medication during the last 4 weeks, with the exceptions ofintranasal, topical, and inhaled corticosteroids or systemic corticosteroids atphysiological doses, which are not to exceeding 10 mg/day of prednisone, or anequivalent corticosteroid,

3. Live attenuated vaccination during the last 4 weeks,

4. Major surgery during the last 4 weeks;

• World Health Organization (WHO) 0 or 1 and Eastern Cooperative Oncology Group (ECOG)Performance Status 0 or 1;

• Patients must have adequate organ function defined as follows:

1. White blood cell count of equal to or higher than 1,500/mm^3,

2. Lymphocyte count of equal to or higher than 800/mm^3,

3. Platelet count of equal to or higher than 100,000/mm^3,

4. Hemoglobin higher than 9 g/dL,

5. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equalto or less than 2.5 upper level norm (or if liver metastases are present mustbe equal to or less than 5x upper level norm)

6. Serum creatinine clearance higher than 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination ofcreatinine clearance;

• Female patients must either be of non-reproductive potential or must have a negativeserum pregnancy test within 3 days prior to the initiation of the study drug.Fertile men with a female partner of childbearing potential must agree to use malecondom plus spermicide and childbearing potential women must have agreed to use atleast one highly effective contraceptive method during treatment on this trial andfor up to 1 month after the last dose of ATRA; Pregnancy testing and contraceptioncounseling should be repeated monthly throughout the period of ATRA treatment.

• Patient should understand, sign, and date the written voluntary informed consentform prior to any protocol-specific procedures performed. Patient should be able andwilling to comply with study visits and procedures as per protocol;

• Patients must be affiliated to a social security system or beneficiary of the same

Exclusion Criteria:

• Evidence of disease rapidly progressing at the time of screening according to thetwo last best-fitted imaging modalities (CT-scans, MRI, positron emissiontomography), at the discretion of the investigator and the multidisciplinary board (RCP);

• Any evidence of brain metastasis;

• Any situation where irradiation of the target site(s) would imply re-irradiation ofa formerly irradiated tumor site;

• Bone metastasis located in a femoral bone if risk of pending fracture is high;

• Liver metastasis adjacent to the stomach or small bowel and liver metastasis thatleads to a volume of uninvolved liver less than 700 cc;

• Patients with any concurrent severe condition (grade 3 or beyond according to CTCAEV5.0) and/or uncontrolled medical condition that could compromise participation inthe study;

• Any psychiatric illness or social situations that would limit compliance with studyrequirements or compromise the ability of the subject to give written informedconsent;

• Active secondary malignancy unless the malignancy is not expected to interfere withthe evaluation of safety and is approved by the Sponsor. Examples of the latterinclude basal or squamous cell carcinoma of the skin, in-situ carcinoma of thecervix, and isolated elevation of prostate-specific antigen. Patients with acompletely treated prior malignancy who are no longer treated (including maintenancetherapy) and no evidence of disease for at least 2 years are eligible;

• Chronic treatment with systemic corticosteroids or another immunosuppressantincluding, but not limited to systemic corticosteroids at doses exceeding 10 mg/dayof prednisone or equivalent, methotrexate, azathioprine, and tumor necrosis factor-α (TNF-α) blockers. Use of immunosuppressive medications for the management ofinvestigational product-related Adverse Events or in subjects with contrastallergies is acceptable. The use of topical, inhaled and intranasal corticosteroidsis permitted;

• Patients with tumor(s) that invade major vessels, as shown unequivocally by imagingstudies;

• Patients with central lung metastasis (i.e within 2 cm from hilum) that are cavitaryas shown unequivocally by imaging studies;

• Persisting significant toxicities related to prior treatments i.e. Grade 2 andhigher adverse event according to CTCAE V5.0 criteria, except for alopecia andbiological values defined in inclusion criteria I6;

• Known allergy or hypersensitivity to the study drug. The study drug iscontraindicated in patients with soy or peanut allergy;

• Positive test for human immunodeficiency virus (HIV) or known acquiredimmunodeficiency syndrome (AIDS);

• Patients at risk of QT prolongation (including patients with hypokaliemia, baselineQT/corrected QT interval more than 470 ms (for women) and more than 450 ms (formen));

• Pregnant or breastfeeding women;

• Persons deprived of their freedom or under guardianship, or for whom it would beimpossible to undergo the medical follow-up required by the trial, for geographic,social or psychological reasons.