Efficacy of Tuvusertib in Recurrent IDH mutant Astrocytoma with ATRX mutation, a phase II prospective trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Investigacion En Neurooncologia

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Dec 2025 → ongoing

Decision date (initial)

2025-11-11

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Grupo Español de Investigación en NeuroOncología

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

The primary objective of this study is to evaluate efficacy of tuvusertib monotherapy in patients with first recurrence of IDH1/2-mutated, ATRX-mutated and p53-mutated astrocytoma by means of progression-free survival (PFS) locally assessed by investigators by magnetic resonance imaging (MRI) following RANO criteria version 2.0

Secondary objectives 10

1. Efficacy secondary objectives ● To evaluate the objective response rate (ORR), defined as the percentage of patients who have achieved complete response (CR), or partial response (PR) as their best response throughout the study locally assessed by investigators and by central radiologists by magnetic resonance imaging (MRI) following RANO criteria v2.0.
2. Efficacy secondary objectives ● To evaluate the median PFS of patients with astrocytomas treated with tuvusertib. PFS is defined as the time from the first tuvusertib dosing date until the first documentation of disease progression following RANO criteria v2.0 or death from any cause, whichever occurs first. The MRI imaging will be assessed by PI and central radiologists.
3. Efficacy secondary objectives ● To evaluate the overall survival (OS) of patients with astrocytomas treated with tuvusertib. OS is defined as the time from the first tuvusertib dosing date to the date of death from any cause.
4. Efficacy secondary objectives ● To evaluate Time to Next Intervention (TTNI) of patients with astrocytomas treated with tuvusertib at recurrence. TTNI is defined as the time from the first tuvusertib dosing date to the initiation of the first subsequent anticancer therapy (surgery, radiotherapy, chemotherapy or any antitumoral systemic treatment).
5. Efficacy secondary objectives ● To evaluate the changes in the neurocognitive function of patients by means of Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT-A and TMT-B), Controlled Oral Word Association Test (COWA), and Neurologic Assessment in Neuro-Oncology Test (NANO) and Mini Mental tests.
6. Efficacy secondary objectives ● To evaluate the changes in the functional status of patients, assessed through the Barthel index and Karnofsky index.
7. Efficacy secondary objectives ● PROs (patients reported outcomes), assessed through the NCI-PRO-CTCAE Custom Survey Questionnaire, and the Patient Global Impression of Change (PGIC) Questionnaire.
8. Safety secondary objectives ● To evaluate safety of the intended treatment regimen based on the frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by national cancer institute common terminology criteria for adverse events (NCI CTCAE v5.0).
9. Exploratory secondary objectives ● Pathologic response in patients of cohort B after 6 weeks of treatment with Tuvusertib, before surgery.
10. Exploratory secondary objectives ● To assess the pharmacokinetic (PK) profile of tuvusertib in patients with gliomas.

Conditions and MedDRA coding

IDH1/2-mutated, ATRX-mutated and p53-mutated astrocytoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.
2. Patients, males and females, ≥ 18 years of age at the time of signing the informed consent.
3. Patients with Karnofsky performance status (KPS) index > 60%
4. Diagnosis of Grade 2-4 astrocytoma, IDH-mutated according to the 2021 WHO classification.
5. 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.
6. Patients must have progressive disease and evaluable disease according to RANO 2.0 criteria. All patients should have MRI contrast enhancement disease.
7. Patients must have undergone previous standard treatment with radiotherapy and chemotherapy (procarbazine, lomustine and vincristine [PCV] or temozolomide [TMZ]).
8. Stable corticosteroid doses during the 2 weeks previous to the first dose of tuvusertib, maximum dose of dexamethasone 4 mg/day or equivalent.
9. 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)
10. 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.
11. Patients able to take oral medications.
12. 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.

Exclusion criteria 13

1. Patients with radiographic recurrence without contrast enhancement by MRI.
2. Leptomeningeal dissemination and/or extracranial metastases.
3. Patients who received more than 1 previous systemic line of treatment for astrocytoma.
4. Patients who received previous treatment with bevacizumab.
5. 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.
6. No prior ATR inhibitor and/or CHK1 inhibitor.
7. 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.
8. 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.
9. Uncontrolled hypertension.
10. 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.
11. Treatment with live or live attenuated vaccine within 30 days of dosing.
12. Known hypersensitivity to the components of tuvusertib.
13. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 11

1. Objective response (ORR) locally assessed by PI according to RANO 2.0.
2. Progression-free survival (PFS) locally assessed by PI according to RANO 2.0.
3. Overall survival (OS).
4. TTNI Time to Next Intervention.
5. Neurocognitive function using HVLT, TMT-A, TMT.B and COWA, and tests.
6. Neurologic status: NANO scale and MMSE test.
7. Functional status: Barthel index and Karnofsky index.
8. Patients reported outcomes through the NCI-PRO-CTCAE Custom Survey and PGIC Questionnaires
9. Adverse events (AE).
10. Treatment-related AEs (TRAEs).
11. Treatment compliance, number of dose reductions / interruptions.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Investigacion En Neurooncologia

Sponsor organisation

Grupo Espanol De Investigacion En Neurooncologia

Address

Calle De Velazquez 7 3a Planta

City

Madrid

Postcode

28001

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Investigacion En Neurooncologia

Contact name

A person designed by the Sponsor

Public contact point

Organisation

Grupo Espanol De Investigacion En Neurooncologia

Contact name

A person designed by the Sponsor

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications