TUVUSERTIB for Astrocytoma (IDH1/2-mutant, ATRX-mutant, p53-mutant)

Inclusion criteria

• {"criterion_text":"- Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities."}
• {"criterion_text":"- Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies. Male participants: Agree to the following during the study intervention period and for at least 3 months after the last dose of tuvusertib: a. Refrain from donating sperm. PLUS, either: b. Abstain from any activity that allows for exposure to ejaculate. OR c. Use a male condom: i. When having sexual intercourse with a woman of childbearing potential (WOCBP), and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, as described in Appendix 4 of study protocol, since a condom may break or leak. ii. Male participants must use a condom with pregnant female partners during the study. Female participants: Are not pregnant or breastfeeding, and at least 1 of the following conditions applies: a. Not a women of childbearing potential (WOCBP) OR b. If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, as described in Appendix 4 of study protocol for the following time periods: i. Before the first dose of tuvusertib, if using hormonal contraception has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses. ii. During the intervention period iii. After the study intervention period for at least 6 months after the last dose of tuvusertib and agree not to donate eggs (ova, oocytes) for reproduction during this period. c. If a WOCBP, have a negative serum pregnancy test, as required by local regulations, within 72 hours before the first dose of tuvusertib."}
• {"criterion_text":"- Patients able to take oral medications."}
• {"criterion_text":"- Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow-up."}
• {"criterion_text":"- Patients, males and females, ≥ 18 years of age at the time of signing the informed consent."}
• {"criterion_text":"- Patients with Karnofsky performance status (KPS) index > 60%"}
• {"criterion_text":"- Diagnosis of Grade 2-4 astrocytoma, IDH-mutated according to the 2021 WHO classification."}
• {"criterion_text":"- Patients must have confirmed ATRX mutation (IHC or NGS sequencing) and p53 mutation (NGS sequencing). Evaluation of CDKN2A also is required by FISH or NGS."}
• {"criterion_text":"- Patients must have progressive disease and evaluable disease according to RANO 2.0 criteria. All patients should have MRI contrast enhancement disease."}
• {"criterion_text":"- Patients must have undergone previous standard treatment with radiotherapy and chemotherapy (procarbazine, lomustine and vincristine [PCV] or temozolomide [TMZ])."}
• {"criterion_text":"- Stable corticosteroid doses during the 2 weeks previous to the first dose of tuvusertib, maximum dose of dexamethasone 4 mg/day or equivalent."}
• {"criterion_text":"- Adequate hematologic, hepatic and renal function as follows: a. Platelet count ≥ 100,000/mm 3 , b. Hemoglobin ≥ 9.0 g/dL, c. Absolute neutrophil count ≥ 1,500/μL with no growth factor treatment within the last 14 days, d. Total bilirubin level ≤ 1.5 × upper limit of normal (ULN) (if Gilbert’s Syndrome may have total bilirubin > 1.5 × ULN), e. Aspartate aminotransferase (AST) level ≤ 3 × ULN, and an alanine aminotransferase (ALT) level ≤ 3 × ULN. f. Serum creatinine ≤ 1.5 × ULN. If serum creatinine is > 1.5 × ULN, creatinine clearance needs to be ≥ 50 mL/min, as estimated by Cockroft-Gault formula: Males: Creatinine CL (mL/min) = Weight (kg) × (140 – Age) 72 x serum creatinine (mg/dL) - Females: Creatinine CL (mL/min) = Weight (kg) × (140 – Age) ×0.85 72 x serum creatinine (mg/dL)"}

Exclusion criteria

• {"criterion_text":"- Patients with radiographic recurrence without contrast enhancement by MRI."}
• {"criterion_text":"- Active and/or uncontrolled infection. The following exceptions apply: a. Participants with HIV infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction b. Participants with evidence of chronic HBV infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have ALT, AST, and total bilirubin levels < ULN, and provided there is no expected drug-drug interaction c. Participants with a history of HCV infection are eligible if they have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels < ULN."}
• {"criterion_text":"- Treatment with live or live attenuated vaccine within 30 days of dosing."}
• {"criterion_text":"- Known hypersensitivity to the components of tuvusertib."}
• {"criterion_text":"- Major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or if the patient has not fully recovered from the surgery within 4 weeks of the study intervention."}
• {"criterion_text":"- Leptomeningeal dissemination and/or extracranial metastases."}
• {"criterion_text":"- Patients who received more than 1 previous systemic line of treatment for astrocytoma."}
• {"criterion_text":"- Patients who received previous treatment with bevacizumab."}
• {"criterion_text":"- Persistence of AEs related to any prior treatments that have not recovered to Grade ≤ 1 unless AEs are clinically nonsignificant (e.g. alopecia) and/or stable on supportive therapy in the opinion of the Investigator."}
• {"criterion_text":"- No prior ATR inhibitor and/or CHK1 inhibitor."}
• {"criterion_text":"- Concurrent treatment with a non permitted drug/intervention: a. Prohibited concomitant medication, as listed in Section 7.8. b. Anticancer treatment within 30 days or 5 half-lives, whichever is shorter, prior to Day 1 of study intervention (6 weeks for nitrosoureas or mitomycin C). c. Prior palliative radiotherapy to metastatic lesion(s) is permitted provided it was completed ≥ 12 weeks prior to study intervention administration and participants have recovered from all related radiotherapy toxicities to Grade ≤ 1. d. Another investigational drug within 30 days or 5 half-lives, whichever is shorter, prior to start of tuvusertib administration. e. Increasing dose of corticoids. f. Received hematopoietic growth factor (e.g., granulocyte colony-stimulating factor, erythropoietin) within 14 days prior to the first dose of tuvusertib."}
• {"criterion_text":"- Significant cardiac disease: a. Unstable angina, myocardial infarction, congestive heart failure ≥ stage II) or a coronary revascularization procedure within 180 days of study entry. b. Calculated QTc average (using the Fridericia correction calculation) of > 450 msec for males and > 470 msec for females."}
• {"criterion_text":"- Uncontrolled hypertension."}

Primary endpoints

• {"endpoint_text":"- The primary endpoint will be the 6-months PFS rate, defined as the proportion of patients alive and free of progression according to RANO 2.0 estimated by Kaplan-Meier at 6 months after the first dose of tuvusertib.","definition_or_measurement_approach":"Proportion of patients alive and free of progression according to RANO 2.0 estimated by Kaplan-Meier at 6 months after the first dose of tuvusertib; PFS assessed by MRI following RANO criteria v2.0 (locally assessed by investigators)."}

Secondary endpoints

• {"endpoint_text":"- Objective response (ORR) locally assessed by PI according to RANO 2.0.","definition_or_measurement_approach":"ORR defined as percentage of patients with complete response (CR) or partial response (PR) as best response, assessed by MRI following RANO criteria v2.0 (local PI assessment and central radiologists per secondary objectives)."}
• {"endpoint_text":"- Progression-free survival (PFS) locally assessed by PI according to RANO 2.0.","definition_or_measurement_approach":"PFS defined as time from first tuvusertib dosing date until first documentation of disease progression per RANO v2.0 or death from any cause (whichever occurs first); MRI assessed by PI and central radiologists."}
• {"endpoint_text":"- Overall survival (OS).","definition_or_measurement_approach":"OS defined as time from first tuvusertib dosing date to date of death from any cause."}
• {"endpoint_text":"- TTNI Time to Next Intervention.","definition_or_measurement_approach":"TTNI defined as time from first tuvusertib dosing date to initiation of first subsequent anticancer therapy (surgery, radiotherapy, chemotherapy or any antitumoral systemic treatment)."}
• {"endpoint_text":"- Neurocognitive function using HVLT, TMT-A, TMT.B and COWA, and tests.","definition_or_measurement_approach":"Assessments by Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT-A and TMT-B), Controlled Oral Word Association Test (COWA), NANO and Mini Mental tests."}
• {"endpoint_text":"- Neurologic status: NANO scale and MMSE test.","definition_or_measurement_approach":"Neurologic status assessed via NANO scale and MMSE."}
• {"endpoint_text":"- Functional status: Barthel index and Karnofsky index.","definition_or_measurement_approach":"Functional status assessed with Barthel index and Karnofsky Performance Status."}
• {"endpoint_text":"- Patients reported outcomes through the NCI-PRO-CTCAE Custom Survey and PGIC Questionnaires","definition_or_measurement_approach":"PROs assessed using NCI-PRO-CTCAE Custom Survey Questionnaire and Patient Global Impression of Change (PGIC)."}
• {"endpoint_text":"- Adverse events (AE).","definition_or_measurement_approach":"Adverse events recorded and reported; safety assessed (see safety objectives referencing NCI CTCAE v5.0 in protocol)."}
• {"endpoint_text":"- Treatment-related AEs (TRAEs).","definition_or_measurement_approach":"TRAEs as per investigator assessment; severity graded per NCI CTCAE v5.0 (safety objectives)."}
• {"endpoint_text":"- Treatment compliance, number of dose reductions / interruptions.","definition_or_measurement_approach":"Compliance measured by dose records; count of dose reductions and interruptions recorded."}

Other endpoints

• {"endpoint_text":"- Pathologic response in patients of cohort B after 6 weeks of treatment with Tuvusertib, before surgery.","definition_or_measurement_approach":"Pathologic response assessed in cohort B after 6 weeks of treatment prior to surgery (exploratory objective as stated)."}
• {"endpoint_text":"- To assess the pharmacokinetic (PK) profile of tuvusertib in patients with gliomas.","definition_or_measurement_approach":"PK profile assessment of tuvusertib in patients with gliomas (exploratory pharmacokinetic objective)."}

Spain

Earliest CTIS Part Ii Submission Date

08-10-2025

Latest Decision Or Authorization Date

11-11-2025

Processing Time Days

34

Number Of Sites

11

Number Of Participants

56

Primary sponsor

Full Name

Grupo Espanol De Investigacion En Neurooncologia

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

Spain