TARLATAMAB for IDH-mutant high-grade glioma | Other high-grade glioma | Other high-grade central nervous system tumors

Inclusion criteria

• {"criterion_text":"- I1.\tPatients aged ≥ 12 years old at time of inform consent signature.\n- I10.\tAdequate pulmonary function as per investigator judgment and no clinically significant pleural effusion. Pleural effusion managed with indwelling pleural catheter (e.g, PleurX) are allowed.\n- I11.\tAvailability 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.\n- I12.\tDiscontinuation of 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: \t≥14 days since small port radiation therapy (i.e. local palliative) \t≥84 days since large-field radiation therapy (i.e. Total body irradiation, craniospinal, whole abdominal, total lung, ≥50% or greater pelvic radiation, ≥50% marrow space) \t≥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\n- I13.\tWomen 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.\n- I14.\tSexually active male must agree to use adequate and appropriate contraception while on study drugs and for 6 months after stopping the study drugs.\n- I15.\tAbility 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.\n- I16.\tCovered by a medical insurance.\n- I2.\tHistologically proven diagnosis of central nervous system (CNS) malignant tumor: IDH-mutant high-grade glioma, other high-grade glioma, or other high-grade CNS tumors.\n- I3.\tTumors 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.\n- I4.\tConfirmed progressive or refractory disease after at least one line of standard therapy containing radiotherapy and for which no further effective standard therapy exists.\n- I5.\tEvaluable or measurable disease as per iRANO criteria\n- I6.\tPerformance status (See Appendix 01): a.\tKarnofsky PS for pediatric patients ≥16 years of age ≥ 70%; b.\tLansky PS for patients between 12 and 15y: ≥ 70%; c.\tPS ECOG for adult patients: 0 or 1.\n- I7.\tLife expectancy ≥ 3 months.\n- I8.\tAdequate end organ function according to laboratory values defined below : *Hematologic criteria •\tPeripheral absolute neutrophil count (ANC) ≥1.5 x 109 /L (without growth factor support within 7 d) •\tPlatelet count ≥ 100 x 109/L (unsupported for > 7 days) •\tHemoglobin ≥ 9.0 g/dL (unsupported for > 7 days) *Renal and hepatic function: •\tCreatinine •\tAdult patient: Creatinine clearance as per CKD-EPI > 30 mL/min/1.73m2 o\tPediatric 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 •\tTotal bilirubin ≤1.5 x ULN (≤ 3.0 × ULN for patients with Gilbert’s syndrome) •\tAlanine 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.\n- I9. Adequate cardiac function defined by Left ventricular ejection fraction (LVEF) ≥50% at baseline."}

Exclusion criteria

• {"criterion_text":"- E1.\tDiagnosis of non-CNS tumor.\n- E10.\tClinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 6 months of C1D1).\n- E11.\tOther 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.\n- E12.\tHistory of hypophysitis or pituitary dysfunction.\n- E13.\tHistory of severe allergic or other hypersensitivity reactions to •\tchimeric or humanized antibodies or fusion proteins, •\tbiopharmaceuticals produced in Chinese hamster ovary cells, •\tor any component of the tarlatamab formulation.\n- E14.\tKnown hypersensitivity to any study drug or component of the formulation or to dacarbazine or TMZ.\n- E15.\tAcute 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.\n- E16.\tArterial thrombosis or a history of pulmonary embolism who need anticoagulants.\n- E17.\tEvidence of interstitial lung disease or active, non-infectious pneumonitis.\n- E18.\tRecurrent 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.\n- E19.\tLive 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.\n- E2.\tDiagnosis of diffuse intrinsic pontine glioma.\n- E20.\tActive 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).\n- E21.\tPatient with documented: ▪ 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\n- E22.\tPrior organ or bone marrow transplant\n- E23.\tHistory 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.\n- E24.\tPregnant or breastfeeding women.\n- E3.\tCurrently treatment with bevacizumab.\n- E4.\tPrior treatment with a DLL3-directed therapy. Note: Prior treatment with TMZ is not an exclusion criteria.\n- E5.\tNeurologically 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.\n- E6.\tEvidence of Grade > 1 recent CNS hemorrhage on the baseline MRI scan.\n- E7.\tBulky tumor on imaging is defined as: i.\tTumor with any evidence of uncial herniation or severe midline shift ii.\tTumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI iii.\tTumor that in the opinion of the investigator shows significant mass effect.\n- E8.\tImpairment 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)\n- E9.\tHistory of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to C1D1."}

Primary endpoints

• {"endpoint_text":"- Phase I: Dose limiting toxicities (DLT) defined as the following adverse event (AE) graded according to NCI CTCAE V5.0 or specific grading system for ICANS and CRS, assessed as related at least to tarlatamab, occurring during the first 2 cycles of treatment (i.e. DLT period is 8 weeks for DL1 or 12 weeks if DL-1 is investigated)","definition_or_measurement_approach":"DLTs graded according to NCI CTCAE V5.0 or specific grading systems for ICANS and CRS; assessed as related to tarlatamab; DLT observation window is the first 2 cycles (8 weeks for DL1 or 12 weeks if DL-1 investigated)."}
• {"endpoint_text":"- Phase II: Objective response rate at 12 weeks (ORR-12W) according to immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria.","definition_or_measurement_approach":"Objective response rate measured at 12 weeks per iRANO criteria."}

Secondary endpoints

• {"endpoint_text":"- •\tDuration of response (DOR) •\tDisease Control Rate (DCR) •\tTime to Objective Response (ToR) •\tProgression Free Survival (PFS) •\tOverall Survival (OS)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Nature, incidence and severity of AEs graded using CTCAE V5.0 or specific grading system for ICANS and CRS","definition_or_measurement_approach":"Adverse events graded per CTCAE V5.0 or specific grading systems for ICANS and CRS; incidence and severity recorded."}
• {"endpoint_text":"- Exploratory endpoint: Gene expression including DLL3 by RNASeq, , ctDNA dosing and sequencing, immunomonitoring on PBMC","definition_or_measurement_approach":"Gene expression assessed by RNASeq (including DLL3); ctDNA sequencing; immunomonitoring performed on PBMCs."}

France

Earliest CTIS Part Ii Submission Date

12-08-2025

Latest Decision Or Authorization Date

22-10-2025

Processing Time Days

71

Number Of Sites

13

Number Of Participants

450

Primary sponsor

Full Name

Centre Leon Berard

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France