Clinical trial NCT06809322: Vorasidenib Maintenance for IDH Mutant Astrocytoma
Official title: Vorasidenib as Maintenance Treatment After First-line Chemoradiotherapy in IDH-mutant Grade 2 or 3 Astrocytoma: a Placebo-controlled, Triple-blind, Randomized Phase III Study (VIGOR)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: IDH-mutant Grade 2 or 3 Astrocytoma
Keywords: Astrocytoma
IDH-mutant grade 2 or 3
Vorasidenib
Placebo- controlled
Triple-blinded
Phase III study
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Canadian Cancer Trials Group
name: Cooperative Trials Group for Neuro-Oncology (COGNO)
First posted: 2025-02-05
Enrollment: 468
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main goal of VIGOR is to demonstrate that vorasidenib maintenance therapy improves locally assessed progression-free survival (PFS) from enrolment compared to placebo in patients with IDH-mutant, CNS5 WHO Grade 2 or 3 astrocytoma following the completion of first-line chemoradiotherapy.

The primary endpoint is Progression-free survival (PFS), as assessed locally from the date of enrolment using the RANO 2.0 criteria.

In this a comparative, randomized (1:1), triple blinded, multicentre phase III superiority trial with one stopping rule for efficacy and futility after end of enrolment, participants in the experimental arm will receive vorasidenib orally once daily at a dose of 40 mg in continuous 28-day cycles while participants in the control arm will receive a matched oral placebo once daily in continuous 28-day cycles

Detailed description: Diffuse gliomas are the most common primary brain tumors in adults and are associated with high morbidity and mortality. Approximately 25% of diffuse gliomas harbour mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes. Among IDH-mutated gliomas, IDH-mutant astrocytoma is the most common diagnosis and occurs mainly in adults in their thirties or forties. Most cases correspond to CNS5 WHO grade 2 and 3, while grade 4 tumors are rare. The prognosis of grade 2 and 3 tumors is significantly better (median overall survival times up to 10 years) than that of grade 4 tumors (median overall survival times around 3-7 years).

According to international guidelines and based on randomized clinical trials, treatment options for IDH-mutated astrocytoma after maximum safe neurosurgical resection include active surveillance or radiotherapy followed by chemotherapy with procarbazine, lomustine and vincristine (PCV) or temozolomide. An active surveillance strategy, however, can be recommended for patients with oligodendroglioma grade 2 or astrocytoma grade 2 with particularly favourable prognostic factors, such as absence of neurological deficits and limited tumor burden. Despite this multimodal treatment, IDH-mutant astrocytomas recur and ultimately lead to patient death, with median progression-free survival times around 7 years and overall survival times of approximately 9-11 years. Novel treatment strategies are needed to extend the survival of these patients.

Recently, the international randomized placebo-controlled phase III INDIGO trial has shown considerable efficacy on progression free survival of the mutant IDH inhibitor vorasidenib in patients with IDH-mutant diffuse grade 2 gliomas that were considered candidates for an active surveillance strategy by the treating physician. Vorasidenib (AG881) is an orally available brain-penetrant dual inhibitor of mutant IDH1 and IDH2 proteins. INDIGO enrolled patients with residual or recurrent non-enhancing grade 2 IDH-mutant glioma who had not received prior radiotherapy or chemotherapy. Participants received either vorasidenib (40 mg once daily) or a matched placebo, given continuously in 28-day cycles. From January 2020 through February 2022, a total of 331 participants were randomly assigned to receive vorasidenib (168 participants) or placebo (163 participants ). The image-based progression-free survival was significantly longer for participants in the vorasidenib group than in the placebo group: 27.7 months (95% CI, 17.0 to non-estimable) vs 11.1 months (95% CI, 11.0-13.7), with a hazard-ratio for disease progression or death of 0.39 (95% CI, 0.27-0.56, p\<0.001). Additionally, time to next intervention was significantly delayed in the vorasidenib group as compared to the placebo group with a hazard ratio of 0.26 (95% CI, 0.15-0.43, p\<0.001). Adverse events leading to treatment interruption occurred in 3.6% of the vorasidenib group and 1.2% of the placebo group. An increased alanine amino transferase level of grade 3 or higher occurred in 9.6% of participants receiving vorasidenib and in none of the participants receiving placebo. Overall, based on the INDIGO trial data, registrational approval by the FDA was granted in August 2024 and EMA approval is expected. Vorasidenib is likely to enter routine clinical practice for patients with IDH-mutant gliomas that do not require immediate chemoradiotherapy.

In the current trial, the investigator will evaluate whether adding vorasidenib as maintenance therapy after completion of standard chemoradiotherapy in patients with astrocytoma, IDH-mutant, CNS5 WHO Grade 2 or 3 prolongs progression-free survival compared to placebo. This trial will also explore the effect of vorasidenib maintenance treatment on overall survival, response rate, time to next intervention, toxicity, health-related quality of life, neurological symptoms, and neurocognitive function. Additionally, this trial will enable translational research through the analysis of tissue samples, liquid biopsies (blood samples), and neuroimaging data.

Overall, VIGOR aims to establish a new standard of care for IDH-mutated, CNS5 WHO Grade 2 or 3 astrocytoma by incorporating maintenance targeted therapy with vorasidenib into the current standard of care chemoradiotherapy.

Eligibility criteria: Inclusion Criteria:

* Before participant's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.
* Age ≥ 18 years
* Integrated diagnosis of astrocytoma, IDH-mutant, WHO CNS5 grade 2 or 3, per local assessment
* Documented IDH1 or IDH2 mutation based on local testing of tumour tissue
* At least 1 prior surgery for glioma (biopsy, partial resection, gross-total resection)
* Completed first-line standard of care radiotherapy (minimum 50.4 Gy, photons or protons allowed) followed by SoC adjuvant chemotherapy (i.e., either 4-12 cycles of temozolomide or 2-6 cycles of PCV).
* Adequate bone marrow function: absolute neutrophil counts ≥ 1.5 x 109/L, haemoglobin ≥ 9 g/dL, platelets 100 x 109/ L.
* Adequate renal function: serum creatinine ≤ 2.0 x ULN, or creatine clearance \> 40 mL/min, as calculated based on CKD-EPI 2021 formula.
* Adequate hepatic function:

  * Total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert's syndrome who are excluded if total bilirubin \> 3.0 × ULN or direct bilirubin ≥1.5 × ULN)
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 x ULN.
  * Alkaline phosphatase (ALP) ≤ 2.5 x ULN.
* Recovered from any clinically relevant toxicity of the previous chemoradiotherapy cycle unless stable and manageable per investigator´s judgement
* WHO performance status 0-2
* Stable or decreasing corticosteroid dose, or no use of corticoids, for at least 7 days prior to enrollment.
* Baseline brain MRI available, as defined in the schedule of assessments
* Available FFPE tumour tissue from prior neurosurgery for central biobanking and translational research
* Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within two weeks prior to enrolment.
* Participants of childbearing / reproductive potential should use two adequate methods of birth control, including a highly effective method and a barrier method during the study treatment period and for at least 90 days after the last dose of treatment.

Exclusion Criteria:

* Presence of 1p19q co-deletion, per local assessment.
* Tumour recurrence or progression per RANO 2.0 criteria between first day of radiotherapy and enrolment, per local assessment
* Last chemotherapy dose of first line chemoradiotherapy less than 6 weeks or more than 12 weeks before enrolment
* Prior therapy with an IDH inhibitor or IDH vaccine
* Any prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
* Integrated diagnosis of astrocytoma, IDH-mutated, CNS5 WHO grade 4
* Pregnancy or breastfeeding
* Significant known active cardiac disease within 6 months before enrollment, including New York Heart Association Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
* Known hypersensitivity to any of the components of vorasidenib.
* Ongoing use of medications that are CYP2C8, CYP2C9, CYP2C19, or CYP3A substrates with a narrow therapeutic index. Participants must be transferred to other medications before receiving the first dose of study drug.
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, known positive human immunodeficiency virus antibody results, or AIDS-related illness.

Participants with a sustained viral response to HCV treatment or immunity to prior HBV infection will be permitted. Participants with chronic HBV that is adequately suppressed by institutional practice will be permitted.

• Known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition that limits the gastrointestinal absorption of drugs administered orally.

Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).

* Inability or known contraindication to undergo contrast media MRI.
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial.

Primary outcomes:
measure: Progression-free survival (PFS) by local assessment
timeFrame: ~7.7 years and 10.5 years from first patient in
Secondary outcomes:
measure: PFS by local assessment
timeFrame: ~7.7 years and 10.5 years from first patient in
measure: Progression-free survival (PFS) from the start of radiotherapy
timeFrame: ~7.7 years and 10.5 years from first patient in
measure: Overall Survival
timeFrame: ~7.7 years and 10.5 years from first patient in
measure: Overall Response
timeFrame: ~7.7 years and 10.5 years from first patient in
measure: Time to next intervention
timeFrame: ~7.7 years and 10.5 years from first patient in
measure: Adverse events
timeFrame: ~7.7 years from first patient in
measure: Health-related Quality of Life QLQ-C30.
timeFrame: ~7.7 years from first patient in
measure: Health-related Quality of Life QLQ-BN20.
timeFrame: ~7.7 years from first patient in
measure: Health-related Quality of Life IADL-BN32
timeFrame: ~7.7 years from first patient in
measure: Health-related Quality of Life item list 46 (IL46)
timeFrame: ~7.7 years from first patient in
measure: Neurocognitive function HVLT-R - Part A Free recall
timeFrame: ~7.7 years from first patient in
measure: Neurocognitive function TMT - Part A
timeFrame: ~7.7 years from first patient in
measure: Neurocognitive function TMT - Part B
timeFrame: ~7.7 years from first patient in
measure: Neurocognitive function COWA
timeFrame: ~7.7 years from first patient in
measure: Neurocognitive function MOS scale
timeFrame: ~7.7 years from first patient in
measure: Neurocognitive function HVLT-R - Part B Delayed recall HVLT-R - Part C Delayed recognition
timeFrame: ~7.7 years from first patient in
measure: Seizure activity
timeFrame: ~7.7 years from first patient in
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Linz
country: Austria
facility: Kepler University Hospital - Neuromed campus
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Leuven
country: Belgium
facility: U.Z. Leuven - Campus Gasthuisberg
city: Brno
country: Czechia
facility: Masaryk Memorial Cancer Institute
city: Bordeaux
country: France
facility: Universitary hospital Bordeaux France
city: Lyon
country: France
facility: CHU Lyon - Hopital neurologique Pierre Wertheimer
city: Marseille
country: France
facility: Marseille APHM
city: Paris
country: France
facility: Assistance Publique Hopitaux de Paris APHP - Sorbonne
city: Toulouse
country: France
facility: Oncopole Claudius Regaud, IUCT-Oncopole
city: Bonn
country: Germany
facility: Universitaskliniken Bonn
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt -Senckenberg Institute of Neurooncology
city: Heidelberg
country: Germany
facility: NNeurology department heidelberg
city: Mannheim
country: Germany
facility: Mannheim University Hospital
city: Regensburg
country: Germany
facility: Universitaetsklinikum Regensburg
city: Bologna
country: Italy
facility: Bellaria Hospital, IRCCS Istituto delle Scienze Neurologiche - AUSL di Bologna
city: Padova
country: Italy
facility: Veneto Institute of Oncology
city: Roma
country: Italy
facility: Sapienza University
city: Torino
country: Italy
facility: AOU Citta della Salute e della Scienza di Torino
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC location VUMC
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Barcelona
country: Spain
facility: Hospital de Sant Pau i La Santa Creu
city: Barcelona
country: Spain
facility: Vall de Hebron Hospital
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Zürich
country: Switzerland
facility: University Hospital Zurich
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital Birmingham
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Surrey Quays
country: United Kingdom
facility: Royal Marsden Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre
Study officials:
affiliation: Universitaetsklinikum Wien - AKH uniklinieken, Vienna, Austria.
name: Matthias Preusser
role: STUDY_CHAIR
affiliation: Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
name: Marjolein Geurts
role: STUDY_CHAIR
References: