This clinical trial is a 2-phase trial designed to evaluate the safety of tarlatamab in combination with a fixed dose of metronomic temozolomide in adolescents and adults with CNS tumors (stratified into two age-based cohorts), and to assess the clinical activity of this therapeutic strategy in three parallel, histology-defined cohorts (IDH-mutant glioma, other gliomas, and other CNS tumors). A pre-screening to detect DLL3 expression by IHC on archival tumor sample must be performed before the therapeutic part. Only patients with DLL3 positive tumor on IHC can be enrolled in the therapeutic part. This pre-screening must be optimally performed during the ongoing treatment line i.e. before documented progression to not delay treatment starts at time of progression. Tumor samples (surgery or biopsy specimen) will be sent to a central lab for IHC testing.

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 that may significantly alter drug absorption of oral drugs e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)

E9. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to C1D1.

E10. Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 6 months of C1D1).

E11. Other malignancy unless this malignancy is not expected to interfere with the evaluation of study endpoints (basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, localized prostate cancer), or with no evidence of disease for ≥ 2 years.

E12.History of hypophysitis or pituitary dysfunction.

E13.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 tarlatamab formulation.

E14.Known hypersensitivity to any study drug or component of the formulation or to dacarbazine or TMZ.

E15.Acute and ongoing toxicities from previous therapy that have not resolved to Grade ≤1, except for alopecia, neuropathy, ototoxicity and lab values presented in inclusion criteria.

E16.Arterial thrombosis or a history of pulmonary embolism who need anticoagulants.

E17.Evidence of interstitial lung disease or active, non-infectious pneumonitis.

E18.Recurrent pneumonitis (grade 2 or higher) or grade≥3 immune-mediated adverse events or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents.

E19. Live vaccines injection within 4 weeks before C1D1. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever and BCG. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.

E20. Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs).

E21. Documentation of:

▪ Active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) unless their HBV is stably controlled on nucleoside analogs (eg entecavir or tenofovir) which will be continued for the duration of the study.

Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to C1D1.

• Active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA, or
• HIV infection

E22. Prior organ or bone marrow transplant

E23. History or current evidence of any condition, co-morbidity, therapy, any active infections, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.

E24. Pregnant or breastfeeding women.