Tuvusertib in Astrocytoma With ATRX Mutation

Summary

The TUVASTRAT study is a phase 2, non-randomized, two.cohort, CRS clinical trial of tuvusertib in patients with first recurrence of IDH1/2-mutated, ATRX-mutated and p53-mutated astrocytoma (Grade 2-4 from WHO classification). The mutational status of IDH (required for diagnosis) is also required. CDKN2A and ATRX will be also determined locally as per standard of care. All enrolled patients should have received first-line chemotherapy and have reported a contrast enhanced PD. Eligible patients are enrolled in two cohorts depending on their eligibility to undergo rescue surgery: * Cohort A: First recurrence of IDH1/2-mutated, ATRX-mutated astrocytoma NOT eligible for rescue surgery. * Cohort B: First recurrence of IDH1/2-mutated, ATRX-mutated astrocytoma candidates to rescue surgery. The primary hypothesis is that treatment with tuvusertib, an ATR inhibitor, will improve the efficacy outcomes and increase the 6-months PFS rate from 45% reported by the standard therapies up to 65% in patients with recurrent IDH-mutated astrocytomas with ATRX mutation. Clinic visits will occur every 3 weeks ±3 days. Tumor assessments by MRI according to RANO 2.0 criteria will be performed at baseline, and every 12 weeks +/-2 weeks (Q12W) until PD, patient withdrawal, start of new treatment line or death. This schedule must be maintained regardless of any delays in dosing. After the first suspect of progression, we recommend a second MRI at 4-8 weeks to confirm the progression, except if there is clinical progression. The MRI imaging will be assessed by PI and central radiologists. The trial includes the assessment of safety (AEs, comorbidities) throughout the study period at every visit, the collection of health-related patient reported outcomes through validated questionnaires at baseline, coincident with the tumor assessments and at the safety visit. Neurologic / neurocognitive status will be assessed through validated tests administered by the physicians. Additionally, ATRX, IDH, P53 and CDK2A mutations will be centrally reviewed in tumor biopsies or archival tumor tissue obtained as close as possible to the baseline. PKs will be determined in sparse peripheral blood samples during the treatment phase. The study includes a data safety monitoring committee (DSMC) to regularly review safety and efficacy. The DSMC will review efficacy and safety at least yearly and more frequently if deemed necessary.

Eligibility

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.

Conditions2

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