PREventing Second Cancers With DOSTARlimab

Inclusion Criteria:

• Male or female patient ≥18 years of age at time of informed consent form signature.Note - Patients with childhood first primary cancer (FPC) are eligible.

• Patients with prior histologically proven primary solid tumors (any type), AJCCstage I, II or III or IV if M0, eligible to curative treatment. Note - Time betweenend of treatment for first cancer and randomisation must be <6 months.

• Patients with at least one risk factor for second primary cancer (SPC) including:

• Exposure to exogenous risk factor : tobacco (>20YP) ≥ 10 years and still active attime of FPC diagnosis and/or Endogenous risk factors (genetic predispositionincluding for instance germ line mutations of p53 or BRCA genes, Lynch syndrome, orany mutations of genes known to be associated with higher risk of cancer accordingto current list from French National Cancer institute or HPV-related FPC.

• Availability of FFPE tumor sample from FPC initial diagnosis for histologicalcomparison in case/at time of SPC. Note - Histological report must be sent to thesponsor with archival FFPE tumor block within 14 days after randomisation.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or .

• Adequate hematologic and end-organ function, defined by the following laboratorytest results:

• WBC ≥ 2.5 x 109/L,

• Hemoglobin ≥ 9.0 g/dL. Patients may be transfused (> 2 weeks before randomisation)to meet this criterion,

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without granulocyte colony-stimulatingfactor support within 2 weeks before randomisation,

• Platelets ≥ 100 x 109/L,

• Lymphocyte count ≥ 0.5 x 109/L;

• Serum creatinine clearance ≥30 mL/min/1.73m2 (MDRD or CKD-EPI formula - SeeAppendix) or serum creatinine ≤1.5 ULN

• Serum bilirubin ≤ 1.5 × Upper Limit of Normal (ULN), with the following exception:Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may beenrolled;

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkalinephosphatase (ALP) ≤ 2.5 x ULN;

• Prothrombin time/INR ≤ 1.5, or, if patient is receiving therapeutic anticoagulation,prothrombin time/INR < 3.0

• aPTT ≤ ULN OR, if patient is receiving therapeutic anticoagulation, aPTT must be < 1.5 ULN. Note: Patient receiving therapeutic anticoagulation must be on stable dose.

• Proteinuria by urine dipstick < 2+ or 24-hour proteinuria ≤ 1.0 g.

• Corrected QT interval (QTc) <450msec (or QTc <480msec for participants with bundlebranch block).

• Women patients of child-bearing potential are eligible, provided they have anegative serum or urine pregnancy and agrees to use adequate contraception for up to 6 months after the final dose of dostarlimab.

• Fertile men must agree to use an effective method of contraception during the studyand for up to 6 months after the last dose of dostarlimab.

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

• Patients must be covered by a medical insurance in country where applicable.

Exclusion Criteria:

• Previous treatment with immunotherapy (any types) for cured first primary cancer.

• Acute and ongoing toxicities from previous therapy that have not resolved to Grade ≤ 1, except for alopecia, neuropathy and lab values presented in inclusion criteria.

• Major surgical procedure, open biopsy, or significant traumatic injury within 28days prior to randomisation, or abdominal surgery, abdominal interventions orsignificant abdominal traumatic injury within 60 days prior to randomisation oranticipation of need for major surgical procedure during the course of the study ornon-recovery from side effects of any such procedure.

• Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-alpha agents) within 2 weeks prior to randomisation, or anticipation ofneed for systemic immunosuppressive medication during study treatment; with theexceptions of intranasal, inhaled, or topical corticosteroids or systemiccorticosteroids at physiological doses, which are not to exceed 10 mg/day ofprednisone, or an equivalent corticosteroid.

• Systemic immunostimulatory agents (including, but not limited to, interferons andIL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever islonger) prior to randomisation.

• Oral or IV antibiotics within 14 days of randomisation.

• History of severe allergic or other hypersensitivity reactions to:

• chimeric or humanized antibodies or fusion proteins,

• biopharmaceuticals produced in Chinese hamster ovary cells, or

• any component of the dostarlimab formulation

• Concurrent treatment with any approved or investigational anti-cancer treatment orparticipation in another clinical trial with therapeutic intent. Note -Hormonotherapy as part of standard of care is allowed.

• History of autoimmune disease including (see Appendix 18.5 for a more comprehensivelist of pre-existing autoimmune diseases and immune deficiencies and exceptions inthe protocol.

• Infectious diseases:

• active infection requiring IV antibiotics,

• severe infection within 4 weeks prior to randomisation, including, but notlimited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia,

• active hepatitis B (chronic or acute; defined as having a positive hepatitis Bsurface antigen [HBsAg] test at screening),

• active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody areeligible only if PCR is negative for HCV RNA at screening,

• HIV infection,

• active tuberculosis,

• influenza vaccination should be given during influenza season. Patients mustnot receive live attenuated influenza vaccine (e.g., FluMist®) within 4 weeksprior to randomisation or at any time during the study.

• Significant cardiovascular disease: see details in the protocol.

• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenicorganizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.

• Evidence of significant uncontrolled concomitant disease that could affectcompliance with the protocol or interpretation of results, including significantliver disease (such as cirrhosis, uncontrolled major seizure disorder, or superiorvena cava syndrome).

• Patient with FPC known to be at high risk of relapse defined as ≥ 70% relapse fromFPC within 2 years.

• Patient patients who are solid organ recipients.

• Patient with primary cancer of unknown origin (CUP).

• Pregnant or lactating women