Grade 2 Glioma, Residual Glioma, Recurrent Glioma
Conditions
Keywords
AG-881
Brief summary
Study AG881-C-004 is a phase 3, multicenter, randomized, double-blind, placebo-controlled study comparing the efficacy of vorasidenib to placebo in participants with residual or recurrent Grade 2 glioma with an IDH1 or IDH2 mutation who have undergone surgery as their only treatment. Participants will be required to have central confirmation of IDH mutation status prior to randomization. Approximately 340 participants are planned to be randomized 1:1 to receive orally administered vorasidenib 40 mg QD or placebo.
Interventions
DRUGVorasidenib
Vorasidenib oral film-coated tablets
DRUGMatching Placebo
Matching Placebo oral tablets
Sponsors
Institut de Recherches Internationales Servier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants randomized in a 1:1 allocation (vorasidenib vs Placebo)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Be at least 12 years of age and weigh at least 40 kg. * Have Grade 2 oligodendroglioma or astrocytoma per WHO 2016 criteria. * Have had at least 1 prior surgery for glioma (biopsy, sub-total resection, gross-total resection), with the most recent surgery having occurred at least 1 year (-1 month) and not more than 5 years (+3 months) before the date of randomization, and no other prior anticancer therapy, including chemotherapy and radiotherapy and not be in need of immediate chemotherapy or radiotherapy in the opinion of the Investigator. * Have confirmed IDH1 (IDH1 R132H/C/G/S/L mutation variants tested) or IDH2 (IDH2 R172K/M/W/S/G mutation variants tested) gene mutation status disease by central laboratory testing during the Prescreening period and available 1p19q status by local testing (eg, fluorescence in situ hybridization \[FISH\], comparative genomic hybridization \[CGH\] array, sequencing) using an accredited laboratory. * Have MRI-evaluable, measurable, non-enhancing disease, as confirmed by the BIRC. * Have a Karnofsky Performance Scale (KPS) score (for participants ≥16 years of age) or Lansky Play Performance Scale (LPPS) score (for participants \<16 years of age) of ≥80%. Key
Exclusion criteria
* Have had any prior anticancer therapy other than surgery (biopsy, sub-total resection, gross-total resection) for treatment of glioma including systemic chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors, investigational agents, laser ablation, etc. * Have features assessed as high-risk by the Investigator, including brainstem involvement either as primary location or by tumor extension, clinically relevant functional or neurocognitive deficits due to the tumor in the opinion of the Investigator (deficits resulting from surgery are allowed), or uncontrolled seizures (defined as persistent seizures interfering with activities of daily life AND failed 3 lines of antiepileptic drug regimens including at least 1 combination regimen).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to approximately 30 months | PFS is defined as the time from date of randomization to date of first documented radiographic PD (as assessed by the blinded independent review committee (BIRC) per modified Response Assessment for Neuro-oncology for Low-Grade Gliomas or date of death due to any cause, whichever occurs earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Growth Rate (TGR) | every 6 months, up to 2 years and 9 months | Calculated as the mean of the percentage change in tumor volume every 6 months |
| Objective Response (OR) as Assessed by the Blinded Independent Review Committee (BIRC) | approximatively 30 months | OR is defined as a best overall response (BOR) of Complete Response, Partial Rresponse, or minor Response as assessed by the BIRC per the modified Response Assessment in Neuro-oncology for Low-grade Gliomas (RANO-LGG). |
| Complete Response (CR) and Partial Response (PR) by BIRC | Approximatively 30 months | CR and PR is defined as a BOR of CR or PR as assessed by BIRC per the modified RANO-LGG |
| Time to Response (TTR) by BIRC | Approximatively 30 months | TTR is defined as the time from the date of randomization to the date of first documented CR, PR, or mR by BIRC per the modified RANO-LGG |
| Time to CR+PR by BIRC | Approximatively 30 months | Time to CR+PR is defined as defined as the time from the date of randomization to the date of first documented CR or PR for subjects with CR or PR per the modified RANO-LGG (by BIRC) |
| Time to Next Intervention (TTNI) | Up to approximately 3 years | TTNI is defined as the time from randomization to the initiation of the first subsequent anticancer therapy (including vorasidenib, for subjects randomized to placebo who subsequently cross over) or death due to any cause. |
| Duration of CR+PR | Approximatively 30 months | Duration of CR+PR is defined as the time from the date of first documented CR or PR to the date of death due to any cause or first documented radiographic PD, whichever occurred earlier |
| Overall Survival (OS) | Approximatively 30 months | OS wad defined as the time from the date of randomization to the date of death due to any cause or data cutoff. |
| Progression-Free Survival (PFS) by the Investigator | Approximatively 30 months | PFS as assessed by the Investigator per the modified RANO-LGG |
| Health-Related Quality of Life (FACT-Br) | Approximatively 30 months | Health-Related Quality of Life (HRQoL) Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 50-item measure comprising the following subscales: Physical Well-Being, Functional Well-Being, Emotional Well-Being, and Social Well-Being subscales from the FACT-General (FACT-G), with the addition of a 23-item brain tumor-specific subscale. These subscales are summed to provide a total score. The total score is given at the end of treatment and total scores range from 0 to 200. Higher scores indicate a better HRQoL |
| Duration of Response (DoR) | Approximatively 30 months | DoR is defined as the time from the date of first documented CR, PR, or mR to the date of death due to any cause or date of first documented radiographic Prgressive Disease, whichever occurred earlier |
Countries
Canada, France, Germany, Israel, Italy, Japan, Netherlands, Spain, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vorasidenib Vorasidenib 40 mg, continuous daily dosing.
Vorasidenib: Vorasidenib oral film-coated tablets | 168 |
| Matching Placebo Matching placebo 40 mg, continuous daily dosing.
Matching Placebo: Matching Placebo oral tablets | 163 |
| Total | 331 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Vorasidenib | Matching Placebo | Total |
|---|---|---|---|
| Age, Continuous | 40.9 years STANDARD_DEVIATION 10.51 | 39.8 years STANDARD_DEVIATION 9.53 | 40.4 years STANDARD_DEVIATION 10.04 |
| Age, Customized Participant Age 12 to less than 16 years old | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Participant Age 16 to less than 18 years old | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized Participant Age 18 to less than 40 years old | 76 Participants | 87 Participants | 163 Participants |
| Age, Customized Participant Age 40 to less than 65 years old | 90 Participants | 74 Participants | 164 Participants |
| Age, Customized Participant Age 65 years or older | 2 Participants | 1 Participants | 3 Participants |
| BMI (kg/m^2) | 26.81 kg/m^2 STANDARD_DEVIATION 5.748 | 26.52 kg/m^2 STANDARD_DEVIATION 5.887 | 26.66 kg/m^2 STANDARD_DEVIATION 5.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 9 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 122 Participants | 135 Participants | 257 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 37 Participants | 19 Participants | 56 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 5 Participants | 8 Participants | 13 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not reported | 33 Participants | 21 Participants | 54 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 125 Participants | 132 Participants | 257 Participants |
| Region of Enrollment Canada | 9 participants | 7 participants | 16 participants |
| Region of Enrollment France | 20 participants | 12 participants | 32 participants |
| Region of Enrollment Germany | 7 participants | 2 participants | 9 participants |
| Region of Enrollment Israel | 25 participants | 16 participants | 41 participants |
| Region of Enrollment Italy | 4 participants | 6 participants | 10 participants |
| Region of Enrollment Netherlands | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Spain | 6 participants | 4 participants | 10 participants |
| Region of Enrollment Switzerland | 8 participants | 1 participants | 9 participants |
| Region of Enrollment United Kingdom | 7 participants | 10 participants | 17 participants |
| Region of Enrollment United States | 77 participants | 100 participants | 177 participants |
| Sex: Female, Male Female | 67 Participants | 77 Participants | 144 Participants |
| Sex: Female, Male Male | 101 Participants | 86 Participants | 187 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 167 | 0 / 163 |
| other Total, other adverse events | 158 / 167 | 152 / 163 |
| serious Total, serious adverse events | 11 / 167 | 8 / 163 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS is defined as the time from date of randomization to date of first documented radiographic PD (as assessed by the blinded independent review committee (BIRC) per modified Response Assessment for Neuro-oncology for Low-Grade Gliomas or date of death due to any cause, whichever occurs earlier.
Time frame: Up to approximately 30 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Progression-Free Survival (PFS) | 27.7 months |
| Matching Placebo | Progression-Free Survival (PFS) | 11.1 months |
p-value: <1e-795% CI: [0.27, 0.56]Kaplan-Meier
Secondary
Complete Response (CR) and Partial Response (PR) by BIRC
CR and PR is defined as a BOR of CR or PR as assessed by BIRC per the modified RANO-LGG
Time frame: Approximatively 30 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorasidenib | Complete Response (CR) and Partial Response (PR) by BIRC | 2 Participants |
| Matching Placebo | Complete Response (CR) and Partial Response (PR) by BIRC | 0 Participants |
Secondary
Duration of CR+PR
Duration of CR+PR is defined as the time from the date of first documented CR or PR to the date of death due to any cause or first documented radiographic PD, whichever occurred earlier
Time frame: Approximatively 30 months
Population: The number of participants with CR or PR was 2 and 0, respectively in the vorasidenib and placebo groups. In the placebo group, no participants experienced the event.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Duration of CR+PR | 13.8 months |
Secondary
Duration of Response (DoR)
DoR is defined as the time from the date of first documented CR, PR, or mR to the date of death due to any cause or date of first documented radiographic Prgressive Disease, whichever occurred earlier
Time frame: Approximatively 30 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Duration of Response (DoR) | 16.6 months |
| Matching Placebo | Duration of Response (DoR) | NA months |
Secondary
Health-Related Quality of Life (FACT-Br)
Health-Related Quality of Life (HRQoL) Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 50-item measure comprising the following subscales: Physical Well-Being, Functional Well-Being, Emotional Well-Being, and Social Well-Being subscales from the FACT-General (FACT-G), with the addition of a 23-item brain tumor-specific subscale. These subscales are summed to provide a total score. The total score is given at the end of treatment and total scores range from 0 to 200. Higher scores indicate a better HRQoL
Time frame: Approximatively 30 months
Population: The low number of participants is related to the measure performed at the end of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorasidenib | Health-Related Quality of Life (FACT-Br) | 150.8 units on a scale | Standard Deviation 29.5 |
| Matching Placebo | Health-Related Quality of Life (FACT-Br) | 151.8 units on a scale | Standard Deviation 31.09 |
Secondary
Objective Response (OR) as Assessed by the Blinded Independent Review Committee (BIRC)
OR is defined as a best overall response (BOR) of Complete Response, Partial Rresponse, or minor Response as assessed by the BIRC per the modified Response Assessment in Neuro-oncology for Low-grade Gliomas (RANO-LGG).
Time frame: approximatively 30 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorasidenib | Objective Response (OR) as Assessed by the Blinded Independent Review Committee (BIRC) | 18 Participants |
| Matching Placebo | Objective Response (OR) as Assessed by the Blinded Independent Review Committee (BIRC) | 4 Participants |
p-value: 0.00395% CI: [1.56, 15.25]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
OS wad defined as the time from the date of randomization to the date of death due to any cause or data cutoff.
Time frame: Approximatively 30 months
Population: This is based off of the participants in the Safety Set, which includes all subjects that received one least one dose of treatment. The months of survival represent the time between randomization and the data cutoff point, since during the study there were no deaths.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Overall Survival (OS) | NA months |
| Matching Placebo | Overall Survival (OS) | NA months |
Secondary
Progression-Free Survival (PFS) by the Investigator
PFS as assessed by the Investigator per the modified RANO-LGG
Time frame: Approximatively 30 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Progression-Free Survival (PFS) by the Investigator | NA months |
| Matching Placebo | Progression-Free Survival (PFS) by the Investigator | 14.1 months |
p-value: 2.4e-795% CI: [0.23, 0.54]Kaplan-Meier
Secondary
Time to CR+PR by BIRC
Time to CR+PR is defined as defined as the time from the date of randomization to the date of first documented CR or PR for subjects with CR or PR per the modified RANO-LGG (by BIRC)
Time frame: Approximatively 30 months
Population: The number of participants with CR or PR was 2 and 0, respectively in the vorasidenib and placebo groups. The median time duration of response is analysed only on participants with response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Time to CR+PR by BIRC | 9.6 months |
Secondary
Time to Next Intervention (TTNI)
TTNI is defined as the time from randomization to the initiation of the first subsequent anticancer therapy (including vorasidenib, for subjects randomized to placebo who subsequently cross over) or death due to any cause.
Time frame: Up to approximately 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Time to Next Intervention (TTNI) | NA months |
| Matching Placebo | Time to Next Intervention (TTNI) | 17.8 months |
Secondary
Time to Response (TTR) by BIRC
TTR is defined as the time from the date of randomization to the date of first documented CR, PR, or mR by BIRC per the modified RANO-LGG
Time frame: Approximatively 30 months
Population: The number of participants with CR, PR or mR was 18 and 4, respectively in the vorasidenib and placebo groups. The median time duration of response is analysed only on participants with response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorasidenib | Time to Response (TTR) by BIRC | 11.0 months |
| Matching Placebo | Time to Response (TTR) by BIRC | 6.9 months |
Secondary
Tumor Growth Rate (TGR)
Calculated as the mean of the percentage change in tumor volume every 6 months
Time frame: every 6 months, up to 2 years and 9 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorasidenib | Tumor Growth Rate (TGR) | -2.5 percent change |
| Matching Placebo | Tumor Growth Rate (TGR) | 13.9 percent change |