Combination of Tarlatamab and Temozolomide in Patients With Central Nervous System Tumors

Inclusion Criteria: I1. Patients aged ≥ 12 years old at time of inform consent signature. I2. Histologically proven diagnosis of central nervous system (CNS) malignant tumor: IDH-mutant high-grade glioma, other high-grade glioma, or other high-grade CNS tumors. I3. Tumors expressing DLL3 based on IHC staining performed on archival tumor sample i.e. at least 1+ on IHC \[patient with no tumor expression of DLL3 are not eligible\]. Note- This pre-screening by IHC should be optimally initiated during an ongoing line of treatment i.e. before documented progression. The ICF1 must be signed before to initiate this pre-screening. I4. Confirmed progressive or refractory disease after at least one line of standard therapy containing radiotherapy and for which no further effective standard therapy exists. I5. Evaluable or measurable disease as per iRANO criteria. I6. Performance status (See Appendix 01): 1. Karnofsky PS for pediatric patients ≥16 years of age ≥ 70%; 2. Lansky PS for patients between 12 and 15y: ≥ 70%; 3. PS ECOG for adult patients: 0 or 1. I7. Life expectancy ≥ 3 months. I8. Adequate end organ function according to laboratory values defined below : Hematologic criteria : * Peripheral absolute neutrophil count (ANC) ≥1.5 G/L (without growth factor support within 7 days) * Platelet count ≥ 100 G/L (unsupported for \> 7 days) * Hemoglobin ≥ 9.0 g/dL (unsupported for \> 7 days) Renal and hepatic function : * Creatinine * Adult patient: Creatinine clearance as per CKD-EPI \> 30 mL/min/1.73 m² * Pediatric patients: Creatinine \<1.5 ULN for age or an estimated glomerular filtration rate (GFR) \> 60 mL/min/1.73m2 GFR based on the Schwartz equation (Mian and Schwartz 2017) or as per institutional guidelines * Total bilirubin ≤1.5 x ULN (≤ 3.0 × ULN for patients with Gilbert's syndrome) * Alanine aminotransferase (ALAT) ≤ 3 x ULN; aspartate aminotransferase (ASAT) ≤ 3 x ULN Coagulation function : Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) ≤ 1.5 x ULN. Patients on chronic anticoagulation therapy who do not meet the criteria above may be eligible to enrol after discussion with the Sponsor. I9. Adequate cardiac function defined by Left ventricular ejection fraction (LVEF) ≥50% at baseline. I10. Adequate pulmonary function as per investigator judgment and no clinically significant pleural effusion. Pleural effusion managed with indwelling pleural catheter (e.g, PleurX) are allowed. I11. Availability of a representative formalin-fixed paraffin-embedded (FFPE) sample of tumor tissue (resection or biopsy, archival) with an associated pathology report must be available. This tumor sample must meet the following quality/quantity control criteria: ≥30 % of tumor cells. I12. Patients must have discontinued all previous anti-cancer treatments (approved or investigational) for CNS treatment with respect of wash-out period at time of C1D1 as shown below: * Cytotoxic and myelosuppressive chemotherapy : ≥21 days (or ≥42 days if prior nitrosourea) * Metronomic chemotherapy regimen : ≥21 days or ≥5 half-lives of the treatment with the longest half-life (whichever is shorter) * Targeted agent : ≥21 days or ≥5 half-lives (whichever is shorter) * Cellular therapy : ≥42 days for any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells) agent * Antibody therapy : ≥21 days after the last infusion except for bevacizumab for which a wash out period of 3 months is requested * Radiotherapy : * ≥14 days since small port radiation therapy (i.e. local palliative) * ≥84 days since large-field radiation therapy (i.e. TBI, craniospinal, whole abdominal, total lung, ≥50% or greater pelvic radiation, ≥50% marrow space) * ≥42 days for other substantial bone marrow radiation * Surgery : Major surgery ≥ 21 days. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48-hour interval must be maintained before C1D1 I13. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior C1D1 and must agree to use highly effective contraceptive measures starting with the Screening Visit through 6 months after the last dose of study drugs and to not breastfeed during this period. Highly effective contraception is defined in Appendix 02. I14. Sexually active male must agree to use adequate and appropriate contraception while on study drugs and for 6 months after stopping the study drugs. I15. Ability to understand and sign informed consent and willingness to comply with the study procedures before study entry and written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines. I16. Covered by a medical insurance. Exclusion Criteria: E1. Diagnosis of non-CNS tumor. E2. Diagnosis of diffuse intrinsic pontine glioma. E3. Current treatment with bevacizumab. E4. Prior treatment with a DLL3-directed therapy. Note: Prior treatment with TMZ is not an exclusion criteria. E5. Neurologically unstable or require increasing doses of corticosteroids during the 7 days before C1D1 or local CNS-directed therapy to control their CNS disease. Note: Patients on low doses of corticosteroids (\< 0.25mg/kg/d of prednisolone or equivalent) during the 7 days prior to receiving study drugs are eligible. E6. Evidence of Grade \> 1 recent CNS hemorrhage on the baseline MRI scan. E7. Bulky tumor on imaging defined as: i. Tumor with any evidence of uncial herniation or severe midline shift ii. Tumor with diameter of \> 6 cm in one dimension on contrast-enhanced MRI iii. Tumor that in the opinion of the investigator shows significant mass effect. E8. Impairment of gastrointestinal (GI) function or GI disease