Clinical Trials List
Protocol NumberM13-813
NCT Number(ClinicalTrials.gov Identfier)NCT02573324
2015-10-15 - 2020-04-22
Phase III
Terminated3
ICD-10C71
Malignant neoplasm of brain
A Randomized, Placebo Controlled Phase 2b/3 Study of ABT-414 with Concurrent Chemoradiation and Adjuvant Temozolomide in Subjects with Newly Diagnosed Glioblastoma Multiforme (GBM) with Epidermal Growth Factor Receptor (EGFR) Amplification. (Intellance1)
-
Trial Applicant
AbbVie
-
Sponsor
AbbVie
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 王瑞鐸 Division of Orthopedics
- 林士傑 Division of Others
- Min-Hsiung Chen Division of Orthopedics
- Yuan-Hung Wu Division of Hematology & Oncology
- 吳智君 Division of Radiology
- 許秉權 Division of Orthopedics
- Yi-Wei Chen Division of Radiation Therapy
- 陳良韋 Division of Radiology
- 張毓帆 Division of Ophthalmology
- YI-JIUN LU Division of Orthopedics
The Actual Total Number of Participants Enrolled
0 Terminated
Linkou Chang Gung Medical Foundation
Taiwan National PI
魏國珍、曾振淦
Co-Principal Investigator
- Pin-Yuan Chen Division of Orthopedics
- 孫銘輝 Division of Radiology
- 陳科廷 Division of Orthopedics
- Peng-Wei Hsu Division of Orthopedics
- 黃盈誠 Division of Orthopedics
- 林亞銳 Division of Orthopedics
- 蔡宏杰 Division of Orthopedics
- 杜振豐 Division of Radiology
- 李承騏 Division of Orthopedics
- Chi-Cheng Chuang Division of Orthopedics
- 蔡悅如 Division of Plastic Surgery
- 盧郁仁 Division of Orthopedics
- 曾振淦 Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
11 Terminated
Audit
None
Co-Principal Investigator
- 黃佩欣 Division of Others
- 王奐之 Division of Orthopedics
- 曾漢民 Division of Orthopedics
- CHANG-PING LIN Division of Ophthalmology
- YA-FANG CHEN Division of Radiology
- 陳婉瑜 Division of Radiation Therapy
- 吳佩芳 Division of Neurology
- 賴詩璠 Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Condition/Disease
Glioblastoma Multiforme (GBM)
Objectives
This study seeks to determine whether the addition of ABT-414 to concomitant radiotherapy and temozolomide (TMZ) followed by combination of ABT-414 with adjuvant TMZ prolongs overall survival (OS) among participants with newly diagnosed glioblastoma (GBM) with epidermal growth factor receptor (EGFR) amplification.
In addition, there is a Phase 1, open-label, multicenter sub-study to assess the pharmacokinetics, safety and tolerability of ABT-414 in participants with newly diagnosed EGFR-amplified GBM who have mild or moderate hepatic impairment.
Test Drug
ABT-414
Active Ingredient
ABT-414
Dosage Form
Injection
Dosage
20 mg
100 mg
100 mg
Endpoints
Primary Outcome Measures :
1. Overall Survival (OS) [ Time Frame: Quarterly After Treatment Discontinuation for Approximately 4 Years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
Secondary Outcome Measures :
1. Progression-Free Survival (PFS) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
PFS will be defined as the number of days from the date of randomization to the date of earliest disease progression based on Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if disease progression does not occur.
2. OS for the O6-methylguaninemethlytransferese (MGMT) Unmethylated Group [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
3. OS for the MGMT Methylated Group [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
4. Time to Deterioration in Symptom Severity Score M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
The MDASI-BT is a participant self-report or interviewer-administered measure used to assess the severity of multiple brain tumor-related symptoms and the impact of these symptoms on daily functioning in the last 24 hours.
5. Time to Deterioration in Symptom Interference Score MDASI-BT [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
The MDASI-BT is a participant self-report or interviewer-administered measure used to assess the severity of multiple brain tumor-related symptoms and the impact of these symptoms on daily functioning in the last 24 hours.
6. Time to Deterioration in Neurocognitive Functioning on the Hopkins Verbal Learning Test Revised (HVLT-R) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
The HVLT-R will assess neurocognitive changes across time.
7. OS for the Epidermal Growth Factor Receptor (EGFR)vIII-Mutated Tumor Subgroup [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
8. PFS for EGFRvIII-Mutated Tumor Subgroup [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
PFS will be defined as the number of days from the date of randomization to the date of earliest disease progression based on Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if disease progression does not occur.
9. Number of Adverse Events (AE) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
1. Overall Survival (OS) [ Time Frame: Quarterly After Treatment Discontinuation for Approximately 4 Years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
Secondary Outcome Measures :
1. Progression-Free Survival (PFS) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
PFS will be defined as the number of days from the date of randomization to the date of earliest disease progression based on Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if disease progression does not occur.
2. OS for the O6-methylguaninemethlytransferese (MGMT) Unmethylated Group [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
3. OS for the MGMT Methylated Group [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
4. Time to Deterioration in Symptom Severity Score M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
The MDASI-BT is a participant self-report or interviewer-administered measure used to assess the severity of multiple brain tumor-related symptoms and the impact of these symptoms on daily functioning in the last 24 hours.
5. Time to Deterioration in Symptom Interference Score MDASI-BT [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
The MDASI-BT is a participant self-report or interviewer-administered measure used to assess the severity of multiple brain tumor-related symptoms and the impact of these symptoms on daily functioning in the last 24 hours.
6. Time to Deterioration in Neurocognitive Functioning on the Hopkins Verbal Learning Test Revised (HVLT-R) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
The HVLT-R will assess neurocognitive changes across time.
7. OS for the Epidermal Growth Factor Receptor (EGFR)vIII-Mutated Tumor Subgroup [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause.
8. PFS for EGFRvIII-Mutated Tumor Subgroup [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
PFS will be defined as the number of days from the date of randomization to the date of earliest disease progression based on Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if disease progression does not occur.
9. Number of Adverse Events (AE) [ Time Frame: Baseline Day 0 Through Approximately 4 years ]
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Inclution Criteria
Main Inclusion:
1. Histologically confirmed de novo Grade IV glioma (GBM or gliosarcoma) or other
subvariants, confirmed by central pathology tissue screening.
2. EGFR amplification in tumor tissue confirmed by central assessment.
3. Supratentorial tumor.
4. The subject must have recovered from the effects of surgery, postoperative infection, and
other complications before enrollment including suture/staple removal from brain surgery
and sufficient wound healing before step 2 registration. Post-operative contrast-enhanced
MRI scan must be done within 72 hours after surgery.
5. ≥ 18 years of age.
6. Karnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomization.
7. Results for required stratification factors (EGFRvIII status, MGMT methylation status, RPA
classs, and region of world) available prior to randomization.
8. Subject has adequate bone marrow, renal, and hepatic function ≤ 21 days prior to
randomization as follows:
Absolute neutrophil count (ANC) ≥ 1,500/mm3
.
Platelets ≥ 100,000/mm3
.
Hemoglobin ≥ 9.0 g/dL.
Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault
formula.
Hepatic function: Total bilirubin, AST, and ALT ≤ 1.5 times upper limit of normal.
9. Electrocardiogram without evidence of acute cardiac ischemia ≤ 21 days prior to
randomization.
10. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least
1 year or surgically sterile by bilateral tubal ligation, bilateral oophorectomy or
hysterectomy) and their male partners should practice at least one accepted method of birth
control listed below during study entry, for the entire duration of the study and for at least 6
months after treatment with ABT-414 and TMZ. In addition to the use of a condom, male
subjects and their female partners of childbearing potential should practice at least one of the
accepted methods of birth control during study and for at least 6 months after ABT-414 and
TMZ.
Total abstinence from sexual intercourse beginning at least one complete menstrual
cycle prior to study drug administration; (of note: sexual abstinence as a method of
contraception should be limited to those cases where it is already established as the
pre-existing lifestyle choice of the subject);
A vasectomized male subject or a vasectomized partner of a female subject;
Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to
study drug administration;
Intrauterine device (females);
Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring
with spermicidal jellies or cream) unless not deemed acceptable as highly effective
contraception by local regulations.
11. Women of child-bearing potential must have a negative pregnancy test (urine or serum)
within 7 days prior to randomization.
12. Must voluntarily sign and date informed consent form, for tumor tissue biomarker testing
and for study participation, approved by an Independent Ethics Committee
(IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or
study-specific procedures.
1. Histologically confirmed de novo Grade IV glioma (GBM or gliosarcoma) or other
subvariants, confirmed by central pathology tissue screening.
2. EGFR amplification in tumor tissue confirmed by central assessment.
3. Supratentorial tumor.
4. The subject must have recovered from the effects of surgery, postoperative infection, and
other complications before enrollment including suture/staple removal from brain surgery
and sufficient wound healing before step 2 registration. Post-operative contrast-enhanced
MRI scan must be done within 72 hours after surgery.
5. ≥ 18 years of age.
6. Karnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomization.
7. Results for required stratification factors (EGFRvIII status, MGMT methylation status, RPA
classs, and region of world) available prior to randomization.
8. Subject has adequate bone marrow, renal, and hepatic function ≤ 21 days prior to
randomization as follows:
Absolute neutrophil count (ANC) ≥ 1,500/mm3
.
Platelets ≥ 100,000/mm3
.
Hemoglobin ≥ 9.0 g/dL.
Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault
formula.
Hepatic function: Total bilirubin, AST, and ALT ≤ 1.5 times upper limit of normal.
9. Electrocardiogram without evidence of acute cardiac ischemia ≤ 21 days prior to
randomization.
10. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least
1 year or surgically sterile by bilateral tubal ligation, bilateral oophorectomy or
hysterectomy) and their male partners should practice at least one accepted method of birth
control listed below during study entry, for the entire duration of the study and for at least 6
months after treatment with ABT-414 and TMZ. In addition to the use of a condom, male
subjects and their female partners of childbearing potential should practice at least one of the
accepted methods of birth control during study and for at least 6 months after ABT-414 and
TMZ.
Total abstinence from sexual intercourse beginning at least one complete menstrual
cycle prior to study drug administration; (of note: sexual abstinence as a method of
contraception should be limited to those cases where it is already established as the
pre-existing lifestyle choice of the subject);
A vasectomized male subject or a vasectomized partner of a female subject;
Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to
study drug administration;
Intrauterine device (females);
Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring
with spermicidal jellies or cream) unless not deemed acceptable as highly effective
contraception by local regulations.
11. Women of child-bearing potential must have a negative pregnancy test (urine or serum)
within 7 days prior to randomization.
12. Must voluntarily sign and date informed consent form, for tumor tissue biomarker testing
and for study participation, approved by an Independent Ethics Committee
(IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or
study-specific procedures.
Exclusion Criteria
Main Exclusion:
1. Subject has multifocal GBM.
2. Gliomatosis cerebri (a diffuse glioma [usually astrocytic] growth pattern consisting of
exceptionally extensive infiltration of a large region of the CNS, with involvement of at least
3 cerebral lobes, usually with bilateral involvement of the cerebral hemispheres and/or deep
grey matter, and frequent extension to the brain stem, cerebellum, and even the spinal cord.)
3. Subject has recurrent GBM.
4. Subject has infratentorial tumor.
5. Subject has metastatic GBM.
6. Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that
prior chemotherapy for a different cancer is allowable, except prior temozolomide.
7. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of
radiation fields.
8. Any prior therapy for glioblastoma (intra-operative techniques to guide resection are allowed
as are experimental imaging techniques).
9. Prior invasive malignancy (except for non-melanomatous skin cancer; carcinoma in situ of
the breast, oral cavity, or cervix) unless disease free for ≥ 2 years.
10. Prior, concomitant, or planned concomitant treatment with NovoTTF, EGFR-targeted
therapy (including EGFRvIII-directed therapy), bevacizumab, Gliadel wafers or other
intratumoral or intracavitary anti-neoplastic therapy, or other experimental therapeutics
intended to treat the tumor; the exceptions are diagnostic or imaging studies, quality of life,
biomarker or epidemiological studies; and operative guides to improve the extent of
resection.
11. Subject has had major immunologic reaction to an IgG-containing agent.
12. Subject has had LASIX (laser-assisted in situ keratomileusis) procedure within the last year.
13. Subject has a history of hypersensitivity to TMZ or excipients, ABT-414 components or
excipients, and dacarbazine (contraindication for TMZ).
14. Subject is unsuitable for receiving ocular steroids:
Subject has any active viral disease of the cornea or conjunctiva, including epithelial
herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella; mycobacterial
infection of the eye; fungal diseases of ocular structures; or any other contraindication
for ocular steroid use.
Subject has a known or suspected hypersensitivity to any ocular steroid.
Subject has primary open angle glaucoma or a history of steroid-induced intraocular
pressure elevation.
15. Subject is a lactating or pregnant female.
16. Severe, active co-morbidity, defined as follows:
Moderate or severe hepatic impairment (Child-Pugh category B or higher [score of 7 or
higher]).
Unstable angina and/or congestive heart failure within the last 6 months.
Transmural myocardial infarction within the last 6 months.
Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations
of ≥ 2 mm using the analysis of an EKG performed within 14 days prior to enrollment.
New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to enrollment.
History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within
6 months.
Serious and inadequately controlled cardiac arrhythmia.
Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or
clinically significant peripheral vascular disease.
Evidence of bleeding diathesis or coagulopathy.
Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula,
gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open
biopsy, or significant traumatic injury within 28 days prior to registration, with the
exception of the craniotomy for tumor resection.
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
enrollment.
Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of enrollment.
Subjects with clinically defined Acquired Immune-Deficiency Syndrome
(AIDS)-defining illness. This is necessary to ensure subjects are likely to be able to
receive the full TMZ regimen.
Active connective tissue disorders, such as lupus or scleroderma that in the opinion of
the Investigator may put the subject at high risk for radiation toxicity.
Any other major medical illnesses or psychiatric impairments that in the Investigator's
opinion will prevent administration or completion of protocol therapy.
17. Subjects treated on any other therapeutic clinical protocols within 30 days prior to study
entry or during participation in the study except intra-operative therapy to guide resection or
experimental imaging without therapeutic intent.
18. Inability to undergo contrast-enhanced MRI scans.
1. Subject has multifocal GBM.
2. Gliomatosis cerebri (a diffuse glioma [usually astrocytic] growth pattern consisting of
exceptionally extensive infiltration of a large region of the CNS, with involvement of at least
3 cerebral lobes, usually with bilateral involvement of the cerebral hemispheres and/or deep
grey matter, and frequent extension to the brain stem, cerebellum, and even the spinal cord.)
3. Subject has recurrent GBM.
4. Subject has infratentorial tumor.
5. Subject has metastatic GBM.
6. Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that
prior chemotherapy for a different cancer is allowable, except prior temozolomide.
7. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of
radiation fields.
8. Any prior therapy for glioblastoma (intra-operative techniques to guide resection are allowed
as are experimental imaging techniques).
9. Prior invasive malignancy (except for non-melanomatous skin cancer; carcinoma in situ of
the breast, oral cavity, or cervix) unless disease free for ≥ 2 years.
10. Prior, concomitant, or planned concomitant treatment with NovoTTF, EGFR-targeted
therapy (including EGFRvIII-directed therapy), bevacizumab, Gliadel wafers or other
intratumoral or intracavitary anti-neoplastic therapy, or other experimental therapeutics
intended to treat the tumor; the exceptions are diagnostic or imaging studies, quality of life,
biomarker or epidemiological studies; and operative guides to improve the extent of
resection.
11. Subject has had major immunologic reaction to an IgG-containing agent.
12. Subject has had LASIX (laser-assisted in situ keratomileusis) procedure within the last year.
13. Subject has a history of hypersensitivity to TMZ or excipients, ABT-414 components or
excipients, and dacarbazine (contraindication for TMZ).
14. Subject is unsuitable for receiving ocular steroids:
Subject has any active viral disease of the cornea or conjunctiva, including epithelial
herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella; mycobacterial
infection of the eye; fungal diseases of ocular structures; or any other contraindication
for ocular steroid use.
Subject has a known or suspected hypersensitivity to any ocular steroid.
Subject has primary open angle glaucoma or a history of steroid-induced intraocular
pressure elevation.
15. Subject is a lactating or pregnant female.
16. Severe, active co-morbidity, defined as follows:
Moderate or severe hepatic impairment (Child-Pugh category B or higher [score of 7 or
higher]).
Unstable angina and/or congestive heart failure within the last 6 months.
Transmural myocardial infarction within the last 6 months.
Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations
of ≥ 2 mm using the analysis of an EKG performed within 14 days prior to enrollment.
New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to enrollment.
History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within
6 months.
Serious and inadequately controlled cardiac arrhythmia.
Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or
clinically significant peripheral vascular disease.
Evidence of bleeding diathesis or coagulopathy.
Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula,
gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open
biopsy, or significant traumatic injury within 28 days prior to registration, with the
exception of the craniotomy for tumor resection.
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
enrollment.
Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of enrollment.
Subjects with clinically defined Acquired Immune-Deficiency Syndrome
(AIDS)-defining illness. This is necessary to ensure subjects are likely to be able to
receive the full TMZ regimen.
Active connective tissue disorders, such as lupus or scleroderma that in the opinion of
the Investigator may put the subject at high risk for radiation toxicity.
Any other major medical illnesses or psychiatric impairments that in the Investigator's
opinion will prevent administration or completion of protocol therapy.
17. Subjects treated on any other therapeutic clinical protocols within 30 days prior to study
entry or during participation in the study except intra-operative therapy to guide resection or
experimental imaging without therapeutic intent.
18. Inability to undergo contrast-enhanced MRI scans.
The Estimated Number of Participants
-
Taiwan
16 participants
-
Global
640 participants
