Adult-type Diffuse Gliomas, Glioblastoma
Conditions
Keywords
glioblastoma, GBM, adult-type diffuse gliomas, gliomas, oligodendroglioma, FGFR1-3 Alteration, FGFR1-3 fusions, FGFR1-3 rearrangements, Central nervous system tumor, isocitrate dehydrogenase, IDH-mutant astocytoma, IDH-wild-type GBM, glioneuronal, neuronal, circumscribed astrocytic glioma
Brief summary
This is an open-label, monotherapy study of pemigatinib in participants with recurrent glioblastoma (GBM) or other recurrent gliomas, circumscribed astrocytic gliomas, and glioneuronal and neuronal tumors with an activating FGFR1-3 mutation or fusion/rearrangement. This study consists of 2 cohorts, Cohorts A, and B, and will enroll approximately 82 participants into each cohort. Participants will receive pemigatinib 13.5 mg QD on a 2-week on-therapy and 1-week off-therapy schedule as long as they are receiving benefit and have not met any criteria for study withdrawal.
Interventions
DRUGPemigatinib
13.5mg tablet taken every morning (unless otherwise directed) for 2 weeks and then 1 week off.
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study consists of 2 cohorts and participants will receive pemigatinib 13.5 mg QD on a 2-week on-therapy and 1-week off-therapy schedule.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Histological, cytological, or molecular confirmation of recurrent GBM or other glioma, circumscribed astrocytic glioma, or glioneuronalor neuronal tumors that has recurred. * Radiographically measurable disease. . -Karnofsky performance status ≥ 60. * Life expectancy ≥ 12 weeks. * Documentation of an actionable FGFR1-3 gene mutation or fusion/rearrangement from tissue : FGFR1-3 fusions or other rearrangements (FGFR1-3 in-frame fusions, any FGFR2 rearrangement, or FGFR1/3 rearrangement with known partner) or a defined FGFR1-3 activating mutation or in-frame deletion. Only participants with FGFR fusions or rearrangements with an intact kinase domain are eligible. * MRI-documented objective progression after prior therapy and must have no therapy available that is likely to provide clinical benefit. * Most recent archival tumor specimen must be a tumor block or a minimum of 15 unstained slides from biopsy or resection of primary tumor or metastasis. * Willingness to avoid pregnancy or fathering children.
Exclusion criteria
* Prior receipt of an FGFR inhibitor. * Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of study drug. * Participants may have had treatment for an unlimited number of prior relapses but must not have had prior bevacizumab or other VEGF/VEGFR inhibitors (exception: prior bevacizumab is allowed if it was administered for the treatment of radiation necrosis rather than progressive tumor and was stopped at least 12 weeks prior to MRI showing tumor progression). * Concurrent anticancer therapy * Candidate for potentially curative surgery. * Dexamethasone (or equivalent) \> 4 mg daily at the time of study registration * Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. * Diffuse leptomeningeal disease. * Radiation therapy administered within 12 weeks before enrollment/first dose of study drug. * Known additional malignancy that is progressing or requires active systemic treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in Participants With Recurrent Glioblastoma Based on Independent Central Review | up to 651 days | ORR was defined as the percentage of participants who achieved a best overall response of complete response (CR) or partial response (PR) based on Response Assessment in Neuro-Oncology (RANO) as determined by an independent centralized radiological review committee. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Confirmed Response Based on Independent Central Review | up to 784 days | Duration of response was defined as the time from the first assessment of confirmed CR or PR until progressive disease (PD) (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose. |
| Duration of Unconfirmed Response Based on Independent Central Review | up to 784 days | Duration of response was defined as the time from the first assessment of unconfirmed CR or PR until progressive disease (PD) (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose. |
| ORR as Determined by Investigator Assessment | up to 784 days | ORR was defined as the percentage of participants who achieved an unconfirmed best overall response of CR or PR based on RANO as determined by investigator assessment. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to 814 days | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib. |
| ORR in Participants With Recurrent Non-glioblastoma Central Nervous System Tumors Based on Independent Central Review | up to 784 days | ORR was defined as the percentage of participants who achieved a best overall response of CR or PR based on RANO as determined by an independent centralized radiological review committee. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically. |
| Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction | up to 814 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib. |
| Disease Control Rate (DCR) Based on Independent Central Review | up to 784 days | DCR was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) based on RANO as determined by an independent centralized radiological review committee. In the case of SD, measurements must have met the SD criteria after the date of the first dose at a minimum interval of 42 days. SD occurred if the participant didn't qualify for CR, PR, or PD and required the following: stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan and clinically stable status. |
| Progression-free Survival (PFS) Based on Independent Central Review | up to 784 days | PFS was defined as the time from the first dose until progressive disease (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose. |
| Overall Survival | up to 784 days | Overall survival was defined as the time from the first dose of study drug to death due to any cause. |
| Number of Participants With Any ≥Grade 3 TEAE | up to 814 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal. |
Countries
Denmark, France, Germany, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
This study was conducted at 31 study centers in Denmark, France, Germany, Italy, Japan, Netherlands, Spain, the United Kingdom, and the United States.
Participants by arm
| Arm | Count |
|---|---|
| Recurrent Glioblastoma Participants with recurrent glioblastoma with defined activating fibroblast growth factor receptor (FGFR) gene alterations received pemigatinib 13.5 milligrams (mg) once daily (QD) on a 2-week on-therapy and 1-week off-therapy schedule as long as they were receiving benefit and had not met any criteria for treatment discontinuation. Defined activating gene alterations included FGFR 1-3 fusions or rearrangements with intact FGFR kinase domain, or a defined set of FGFR 1-3 activating mutations or in-frame deletions. | 74 |
| Recurrent Non-glioblastoma CNS Tumors Participants with recurrent non-glioblastoma central nervous system (CNS) tumors with defined activating FGFR gene alterations received pemigatinib 13.5 milligrams (mg) once daily (QD) on a 2-week on-therapy and 1-week off-therapy schedule as long as they were receiving benefit and had not met any criteria for treatment discontinuation. Defined activating gene alterations included FGFR 1-3 fusions or rearrangements with intact FGFR kinase domain, or a defined set of FGFR 1-3 activating mutations or in-frame deletions. | 9 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 50 | 2 |
| Overall Study | Study terminated by Sponsor | 24 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Recurrent Glioblastoma | Recurrent Non-glioblastoma CNS Tumors | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 11.45 | 39.2 years STANDARD_DEVIATION 12.75 | 55.1 years STANDARD_DEVIATION 12.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 6 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 3 Participants | 16 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black/African-American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Captured as Other in Database | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 7 Participants | 1 Participants | 8 Participants |
| Race/Ethnicity, Customized Unknown | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized White/Caucasian | 58 Participants | 6 Participants | 64 Participants |
| Sex: Female, Male Female | 30 Participants | 3 Participants | 33 Participants |
| Sex: Female, Male Male | 44 Participants | 6 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 50 / 74 | 2 / 9 | 52 / 83 |
| other Total, other adverse events | 71 / 74 | 9 / 9 | 80 / 83 |
| serious Total, serious adverse events | 17 / 74 | 0 / 9 | 17 / 83 |
Outcome results
Primary
Objective Response Rate (ORR) in Participants With Recurrent Glioblastoma Based on Independent Central Review
ORR was defined as the percentage of participants who achieved a best overall response of complete response (CR) or partial response (PR) based on Response Assessment in Neuro-Oncology (RANO) as determined by an independent centralized radiological review committee. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically.
Time frame: up to 651 days
Population: Full Analysis Set: all enrolled participants who received at least 1 dose of pemigatinib. The 95% confidence interval (CI) was calculated based on the exact method for binomial distribution.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recurrent Glioblastoma | Objective Response Rate (ORR) in Participants With Recurrent Glioblastoma Based on Independent Central Review | Confirmed tumor responses | 5.4 percentage of participants |
| Recurrent Glioblastoma | Objective Response Rate (ORR) in Participants With Recurrent Glioblastoma Based on Independent Central Review | Unconfirmed tumor responses | 8.1 percentage of participants |
Secondary
Disease Control Rate (DCR) Based on Independent Central Review
DCR was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) based on RANO as determined by an independent centralized radiological review committee. In the case of SD, measurements must have met the SD criteria after the date of the first dose at a minimum interval of 42 days. SD occurred if the participant didn't qualify for CR, PR, or PD and required the following: stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan and clinically stable status.
Time frame: up to 784 days
Population: Full Analysis Set. The 95% CIs were calculated based on the exact method for binomial distribution.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recurrent Glioblastoma | Disease Control Rate (DCR) Based on Independent Central Review | Confirmed tumor responses | 36.5 percentage of participants |
| Recurrent Glioblastoma | Disease Control Rate (DCR) Based on Independent Central Review | Unconfirmed tumor responses | 36.5 percentage of participants |
| Recurrent Non-glioblastoma CNS Tumors | Disease Control Rate (DCR) Based on Independent Central Review | Confirmed tumor responses | 66.7 percentage of participants |
| Recurrent Non-glioblastoma CNS Tumors | Disease Control Rate (DCR) Based on Independent Central Review | Unconfirmed tumor responses | 66.7 percentage of participants |
Secondary
Duration of Confirmed Response Based on Independent Central Review
Duration of response was defined as the time from the first assessment of confirmed CR or PR until progressive disease (PD) (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.
Time frame: up to 784 days
Population: Full Analysis Set. Only those participants with a confirmed CR or PR were analyzed. The 95% CIs were calculated using the Brookmeyer and Crowley method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recurrent Glioblastoma | Duration of Confirmed Response Based on Independent Central Review | NA months |
| Recurrent Non-glioblastoma CNS Tumors | Duration of Confirmed Response Based on Independent Central Review | NA months |
Secondary
Duration of Unconfirmed Response Based on Independent Central Review
Duration of response was defined as the time from the first assessment of unconfirmed CR or PR until progressive disease (PD) (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.
Time frame: up to 784 days
Population: Full Analysis Set. Only those participants with an unconfirmed CR or PR were analyzed. The 95% CIs were calculated using the Brookmeyer and Crowley method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recurrent Glioblastoma | Duration of Unconfirmed Response Based on Independent Central Review | NA months |
| Recurrent Non-glioblastoma CNS Tumors | Duration of Unconfirmed Response Based on Independent Central Review | NA months |
Secondary
Number of Participants With Any ≥Grade 3 TEAE
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.
Time frame: up to 814 days
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recurrent Glioblastoma | Number of Participants With Any ≥Grade 3 TEAE | 27 Participants |
| Recurrent Non-glioblastoma CNS Tumors | Number of Participants With Any ≥Grade 3 TEAE | 3 Participants |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib.
Time frame: up to 814 days
Population: Safety Population: all enrolled participants who received at least 1 dose of pemigatinib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recurrent Glioblastoma | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 73 Participants |
| Recurrent Non-glioblastoma CNS Tumors | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 9 Participants |
Secondary
Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib.
Time frame: up to 814 days
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Recurrent Glioblastoma | Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction | TEAEs leading to discontinuation of pemigatinib | 2 Participants |
| Recurrent Glioblastoma | Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction | TEAEs leading to pemigatinib dose interruption | 22 Participants |
| Recurrent Glioblastoma | Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction | TEAEs leading to pemigatinib dose reduction | 5 Participants |
| Recurrent Non-glioblastoma CNS Tumors | Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction | TEAEs leading to discontinuation of pemigatinib | 0 Participants |
| Recurrent Non-glioblastoma CNS Tumors | Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction | TEAEs leading to pemigatinib dose interruption | 4 Participants |
| Recurrent Non-glioblastoma CNS Tumors | Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction | TEAEs leading to pemigatinib dose reduction | 2 Participants |
Secondary
ORR as Determined by Investigator Assessment
ORR was defined as the percentage of participants who achieved an unconfirmed best overall response of CR or PR based on RANO as determined by investigator assessment. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically.
Time frame: up to 784 days
Population: Full Analysis Set. The 95% CIs were calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent Glioblastoma | ORR as Determined by Investigator Assessment | 8.1 percentage of participants |
| Recurrent Non-glioblastoma CNS Tumors | ORR as Determined by Investigator Assessment | 22.2 percentage of participants |
Secondary
ORR in Participants With Recurrent Non-glioblastoma Central Nervous System Tumors Based on Independent Central Review
ORR was defined as the percentage of participants who achieved a best overall response of CR or PR based on RANO as determined by an independent centralized radiological review committee. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically.
Time frame: up to 784 days
Population: Full Analysis Set. The 95% CI was calculated based on the exact method for binomial distribution.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recurrent Non-glioblastoma CNS Tumors | ORR in Participants With Recurrent Non-glioblastoma Central Nervous System Tumors Based on Independent Central Review | Confirmed tumor responses | 22.2 percentage of participants |
| Recurrent Non-glioblastoma CNS Tumors | ORR in Participants With Recurrent Non-glioblastoma Central Nervous System Tumors Based on Independent Central Review | Unconfirmed tumor responses | 22.2 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the time from the first dose of study drug to death due to any cause.
Time frame: up to 784 days
Population: Full Analysis Set. The 95% CIs were calculated using the Brookmeyer and Crowley method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recurrent Glioblastoma | Overall Survival | 11.37 months |
| Recurrent Non-glioblastoma CNS Tumors | Overall Survival | 24.08 months |
Secondary
Progression-free Survival (PFS) Based on Independent Central Review
PFS was defined as the time from the first dose until progressive disease (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.
Time frame: up to 784 days
Population: Full Analysis Set. The 95% CIs were calculated using the Brookmeyer and Crowley method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recurrent Glioblastoma | Progression-free Survival (PFS) Based on Independent Central Review | 2.07 months |
| Recurrent Non-glioblastoma CNS Tumors | Progression-free Survival (PFS) Based on Independent Central Review | NA months |