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

Exclusion Criteria

• •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.
• •E1. Diagnosis of non-CNS tumor.
• •E2. Diagnosis of diffuse intrinsic pontine glioma.
• •E3. Current treatment with bevacizumab.
• •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.