Astrocytoma
Conditions
Keywords
Tuvusertib, Astrocytoma, IDH mutated, ATRX mutated
Brief 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.
Interventions
DRUGTuvusertib
All patients will receive tuvusertib at the recommended dose (for) expansion (RDE) of 180 mg daily (QD) during 2 weeks on and 1 week off.
Sponsors
Grupo Español de Investigación en Neurooncología
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-months progression-free survival (PFS) rate | At 6 months after the first dose of tuvusertib | defined as the proportion of patients alive and free of progression according to RANO 2.0 estimated by Kaplan-Meier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response (ORR) | Throughout the study period, approximately an average of 2 year | 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 |
| Progression-free survival (PFS) | Throughout the study period, approximately an average of 2 year | defined as the time from the first tuvusertib dosing date until the first documentation of disease progression or death from any cause, whichever occurs first. This endpoint will be locally assessed by investigators by magnetic resonance imaging (MRI) following RANO criteria v2.0. The median estimated by kaplan-Meier will be reported. |
| Overall survival (OS) | Throughout the study period, approximately an average of 2 year | defined as the time from the first tuvusertib dosing date to the date of death from any cause. The median estimated by kaplan-Meier will be reported. |
| Time to Next Intervention (TTNI) | Throughout the study period, approximately an average of 2 year | 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) |
| Neurocognitive function changes by Hopkins Verbal Learning Test-Revised (HVLT-R) | Throughout the study period, approximately an average of 2 year | Patients are assessed by means of validated neurocognition tests: Hopkins Verbal Learning Test-Revised (HVLT-R). A numerical value is attributed to each patient in baseline and the changes of that in subsequent assessments will be calculated as percentage decrease / increase. Here we report the number of patients experiencing an increase (better) or decrease (worse) in their neurocognitive function throughout the study. |
| Neurocognitive function changes by Trail Making Test (TMT-A and TMT-B) | Throughout the study period, approximately an average of 2 year | Patients are assessed by means of validated neurocognition tests: Trail Making Test (TMT-A and TMT-B). A numerical value is attributed to each patient in baseline and the changes of that in subsequent assessments will be calculated as percentage decrease / increase. Here we report the number of patients experiencing an increase (better) or decrease (worse) in their neurocognitive function throughout the study. |
| Neurocognitive function changes by , Controlled Oral Word Association Test (COWA) | Throughout the study period, approximately an average of 2 year | Patients are assessed by means of validated neurocognition tests: Controlled Oral Word Association Test (COWA). A numerical value is attributed to each patient in baseline and the changes of that in subsequent assessments will be calculated as percentage decrease / increase. Here we report the number of patients experiencing an increase (better) or decrease (worse) in their neurocognitive function throughout the study. |
| Neurologic status changes by Mini Mental Test | Throughout the study period, approximately an average of 2 year | Patients are assessed by means of validated Neurologic Assessment in Mini Mental tests. A numerical value is attributed to each patient in baseline and the changes of that in subsequent assessments will be calculated as percentage decrease / increase. Here we report the number of patients experiencing an increase (better) or decrease (worse) in their neurologic status throughout the study. |
| Neurologic status changes by Neuro-Oncology Test | Throughout the study period, approximately an average of 2 year | Patients are assessed by means of validated Neurologic Assessment in Neuro-Oncology Test (NANO). A numerical value is attributed to each patient in baseline and the changes of that in subsequent assessments will be calculated as percentage decrease / increase. Here we report the number of patients experiencing an increase (better) or decrease (worse) in their neurologic status throughout the study. |
| Functional status changes | Throughout the study period, approximately an average of 2 year | Patients are assessed by means of Barthel test and Karnofsky performance status (KPS) scale. A numerical value is attributed to each patient in baseline and the changes of that in subsequent assessments will be calculated as percentage decrease / increase. Here we report the number of patients experiencing an increase (better) or decrease (worse) in their functional status throughout the study. |
| Treatment compliance | Throughout the study period, approximately an average of 2 year | Number of patients who experience tuvusertib dose delays and interruptions due to toxicities |
| Global quality of life (QoL) changes | Throughout the study period, approximately an average of 2 year | assessed through the national cancer institute (NCI) - patient reported outcomes (PRO) -Common terminology Criteria for Adverse Events (CTCAE) Custom Survey questionnaire, and the Patient Global Impression of Change (PGIC) questionnaire. A numerical value is attributed to each patient in baseline and the changes of that in subsequent assessments will be calculated as percentage decrease / increase. Here we ONLY report the number of patients experiencing an increase (better) or decrease (worse) in their global QoL Score, being an unique measure or endpoint. The global value is to be reported, no more than one outcome. |
Countries
Spain
Contacts
CONTACTGEINO Secretary
STUDY_CHAIREstela Pineda, M.D.; Ph.D.
Medical Oncology, Hospital Clínic de Barcelona
STUDY_CHAIRMaria Vieito, M.D.; Ph.D.
Medical Oncology, Hospital Universitari Vall d'Hebrón
Outcome results
None listed