Tuvusertib for ATRX‑mutated IDH‑mutant astrocytoma

Efficacy of Tuvusertib in Recurrent IDH Mutant Astrocytoma With ATRX Mutation, a Phase II Prospective Trial.

This trial will test the ATR inhibitor tuvusertib in adults with first‑recurrent IDH‑ and ATRX‑mutant, p53‑mutant astrocytoma to see if it delays tumor progression.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 56 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Grupo Español de Investigación en Neurooncología (Academic / other)
• Drugs / interventions: bevacizumab, chemotherapy
• Locations: 10 sites (Palma de Mallorca, Balearic Islands and 9 other locations)
• Trial ID: NCT07417761 on ClinicalTrials.gov

What this trial studies

This is a phase 2, non‑randomized trial that gives tuvusertib to adults with first recurrence of IDH‑mutant, ATRX‑mutant and p53‑mutant astrocytoma who have contrast‑enhancing progressive disease after prior radiotherapy and chemotherapy. Participants are assigned to one of two cohorts based on whether they are candidates for rescue surgery, and local testing for ATRX, IDH, p53 and CDKN2A is required per standard of care. The protocol aims to raise the 6‑month progression‑free survival rate from about 45% with standard approaches to approximately 65% with tuvusertib. Key eligibility includes age ≥18, KPS >60, prior first‑line chemotherapy, and radiographic progression by RANO 2.0.

Who should consider this trial

Good fit: Adults (≥18) with WHO grade 2–4, IDH‑mutant astrocytoma who have confirmed ATRX and p53 mutations, prior radiotherapy and chemotherapy, KPS >60, and contrast‑enhancing first recurrence are the intended participants, with cohort assignment based on eligibility for rescue surgery.

Not a fit: Patients who lack the required IDH/ATRX/p53 mutations, have poor performance status, lack contrast‑enhancing disease, or have other immediate surgical options are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, tuvusertib could increase progression‑free survival and delay recurrence for patients with ATRX‑mutant astrocytoma.

How similar studies have performed: ATR inhibitors have shown promising preclinical activity and limited early‑phase clinical signals in related cancers, but their use specifically in ATRX‑mutant astrocytoma remains relatively novel.

Eligibility criteria

Inclusion Criteria:

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% (Appendix 5).
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:

   1. Platelet count ≥ 100,000/mm3,
   2. Hemoglobin ≥ 9.0 g/dL,
   3. Absolute neutrophil count ≥ 1,500/μL with no growth factor treatment within the last 14 days,
   4. Total bilirubin level ≤ 1.5 × upper limit of normal (ULN) (if Gilbert's Syndrome may have total bilirubin \> 1.5 × ULN),
   5. Aspartate aminotransferase (AST) level ≤ 3 × ULN, and an alanine aminotransferase (ALT) level ≤ 3 × ULN.
   6. Serum creatinine ≤ 1.5 × ULN. If serum creatinine is \> 1.5 × ULN, creatinine clearance needs to be ≥ 50 mL/min, as estimated by Cockcroft-Gault
10. Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
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:

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:

   1. Prohibited concomitant medication, as listed in Section 7.8.
   2. 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).
   3. 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.
   4. Another investigational drug within 30 days or 5 half-lives, whichever is shorter, prior to start of tuvusertib administration.
   5. Increasing dose of corticoids.
   6. 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:

   1. Unstable angina, myocardial infarction, congestive heart failure ≥ stage II) or a coronary revascularization procedure within 180 days of study entry.
   2. Calculated QTc average (using the Fridericia correction calculation) of \> 450 msec for males and \> 470 msec for females.
   3. Uncontrolled hypertension.
9. Active and/or uncontrolled infection. The following exceptions apply:

   1. 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
   2. 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
   3. 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.

Where this trial is running

Palma de Mallorca, Balearic Islands and 9 other locations

• Hospital Universitario Son Espases — Palma de Mallorca, Balearic Islands, Spain (Recruiting)
• Hospital Universitario Vall d'Hebron — Barcelona, Barcelona, Spain (Recruiting)
• Hospital Clinic de Barcelona — Barcelona, Barcelona, Spain (Recruiting)
• Hospital Universitario de Cruces — Barakaldo, Bizkaia, Spain (Recruiting)
• Hospital Universitario Virgen de las Nieves — Granada, Granada, Spain (Recruiting)
• Hospital Universitario Ramón y Cajal — Madrid, Madrid, Spain (Recruiting)
• Hospital Álvaro Cunqueiro — Vigo, Pontevedra, Spain (Recruiting)
• Hospital Clínico Universitario de Salamanca — Salamanca, Salamanca, Spain (Not_yet_recruiting)
• Hospital Universitario Virgen del Rocío — Seville, Sevilla, Spain (Recruiting)
• Hospital Clínico Universitario de Valencia - INCLIVA — Valencia, Valencia, Spain (Recruiting)

Study contacts

• Study coordinator: GEINO Secretary

Conditions Astrocytoma; Tuvusertib; IDH mutated; ATRX mutated