A Randomized, Placebo Controlled Phase 2b/3 Study of ABT-414 with Concurrent Chemoradiation and Adjuvant Temozolomide in Subjects with Newly Diagnosed Glioblastoma (GBM) with Epidermal Growth Factor Receptor (EGFR) Amplification (Intellance 1)
The goal of the pre-screening part of this clinical research study is to learn if you are eligible to be screened to take part in the main research study. The goal of the main part of this clinical research study is to learn if adding ABT-414 to radiation therapy and temozolomide can help to control glioblastoma better than treatment with radiation therapy and temozolomide alone. The safety of the combinations will also be studied.
Disease Group: Malignant neoplasms of eye brain and other parts of central nervous system
Treatment Agent: ABT-414,Temozolomide
Treatment Location: Both at MDACC & and Other Sites
Sponsor: AbbVie Inc.
1. Primary Objective Phase 2b: To determine whether the addition of ABT-414 to concomitant radiotherapy and temozolomide plus adjuvant temozolomide prolongs Progression Free Survival (PFS) among subjects with newly diagnosed GBM harboring EGFR amplification. Phase 3: To determine whether the addition of ABT-414 to concomitant radiotherapy and temozolomide plus adjuvant temozolomide prolongs Overall Survival (OS) among subjects with newly diagnosed GBM harboring EGFR amplification. 2. Secondary Objectives To determine whether the addition of ABT-414 to concomitant radiotherapy and temozolomide plus adjuvant temozolomide improves outcomes among subjects with newly diagnosed GBM harboring EGFR amplification for the following endpoints: PFS (secondary endpoint for Phase 3) OS (secondary endpoint for Phase 2b) OS for the EGFRvIII-mutated tumor subgroup PFS for EGFRvIII-mutated tumor subgroup Time to deterioration in symptom severity score M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Time to deterioration in symptom interference score (MDASI-BT) Time to deterioration in neurocognitive functioning on the Hopkins Verbal Learning Test Revised (HVLT-R) Safety: Assessment of comparative safety 3. Exploratory Objectives To determine whether the addition of ABT-414 to concomitant radiotherapy and temozolomide plus adjuvant temozolomide improves outcomes among subjects with newly diagnosed GBM harboring EGFR amplification for the following endpoints: OS at 1 year OS at 2 years PFS at 1 year PFS at 2 years OS for non-EGFRvIII subjects (comparison between arms) PFS for non-EGFRvIII subjects (comparison between arms) OS and PFS for Total EGFR expressions levels EGFRvIII status (as a prognostic factor independent of treatment assignment) overall and among molecular subgroups Time to deterioration in HRQoL European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30/BN20 scale scores) Change from baseline in HRQoL (EORTC QLQ-C30/BN20 scale scores) Change from baseline in symptom severity factor groupings (MDASI-BT neurologic, cognitive, and treatment) Time to deterioration in performance status Karnofsky Performance Status (KPS) Change from baseline in performance status (KPS) Median time KPS score was maintained at 70 or higher Time to deterioration in neurocognitive functioning on Controlled Oral Word Association ( COWA-FAS) Change from baseline in neurocognitive functioning (HVLT-R and COWA-FAS) Change from baseline in Vision item on the MDASI-BT and EORTC BN20 Change from baseline in health status (EQ-5D-5L and EQ-5D-VAS) Changes in EGFR molecular profile during therapy among subjects who undergo additional surgery as part of routine care Pharmacokinetics of ABT-414, total ABT-806, and unconjugated cys-mcMMAF To determine the relationship of neurocognitive function (HVLT-R, COWA-FAS) and patient reported outcomes (PRO) (EORTC QLQ-C30/BN 20, MDASI-BT) with progression-free and overall survival To determine the association between tumor molecular profile and neurocognitive function (HVLT-R, COWA-FAS) and PROs (EORTC QLQ-C30/BN 20, MDASI-BT) Change from maximum corticosteroid dosing
IRB Review and Approval Date: 06/07/2016
Recruitment Status: Open
Projected Accrual: 720
1) Histologically confirmed de novo Grade IV glioma (GBM, gliosarcoma or
other subvariants) confirmed by central pathology tissue screening.
2) EGFR amplification in tumor tissue confirmed by central assessment.
3) 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 randomization.
4) >/= 18 years of age.
5) Karnofsky performance status >/= 70 at assessment </=14 days prior to randomization.
6) Results for required stratification factors (EGFRvIII status, MGMT methylation status, Recursive Partitioning Analysis (RPA) class, and region of world) available prior to randomization.
7) Subject has adequate bone marrow, renal, and hepatic function </= 21 days prior to randomization as follows: a) Absolute neutrophil count (ANC) >/= 1,500/mm3; b) Platelets >/= 100,000/mm3; c) Hemoglobin (Hgb) >/= 9.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb >/= 9.0 g/dL is acceptable.); d) Renal function: calculated creatinine clearance >/= 30 mL/min by the Cockcroft-Gault formula; e) Hepatic function: Total bilirubin < 1.5 times upper limit of normal (ULN), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) </= 3 times upper limit of normal (ULN). Subjects with Gilbert's syndrome documented in medical history may be enrolled if total bilirubin is < 3 times ULN.
8) Electrocardiogram (ECG) without evidence of acute cardiac ischemia </= 21 days prior to randomization.
9) Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least 1 year or surgically sterile by bilateral salpingectomy, bilateral oophorectomy or hysterectomy) 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: treatment has ended. Male subjects 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. If using a condom, practice at least one other method of birth control listed below during the study and for at least 6 months after ABT-414 and TMZ: Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 1 month prior to Study Day 1;
10) (9. continued) Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, initiated at least 1 month prior to Study Day 1; Bilateral tubal occlusion/ligation; True abstinence: Refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject [periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable]; • 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, IUD (females); Intrauterine hormone-releasing system, IUS (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) Subject has multifocal GBM defined as discrete sites of disease
without contiguous T2/FLAIR abnormality that require distinct
radiotherapy ports. Satellite lesions that are associated with a
contiguous area of T2/FLAIR abnormality as the main lesion(s) and that
are encompassed within the same radiotherapy port as the main lesion(s)
2) Subject has recurrent GBM.
3) Subject has metastatic GBM.
4) 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.
5) Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields.
6) Any prior therapy for glioblastoma, except surgery (intra-operative techniques to guide resection are allowed as are experimental imaging techniques).
7) 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.
8) Prior, concomitant, or planned concomitant treatment with anti-neoplastic intent including but not limited to NovoTumor Treatment Fields (Novo TTF), 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. Diagnostic or imaging studies; quality of life; biomarker or epidemiological studies; and operative guides to improve extent of resection are allowed.
9) Subject has had major immunologic reaction to an IgG-containing agent.
10) Subject has had LASIK (laser-assisted in situ keratomileusis) procedure within the last 1 year or cataract surgery within the last 3 months.
11) Subject has a history of hypersensitivity to TMZ or excipients, ABT-414 components or excipients, and dacarbazine (contraindication for TMZ).
12) 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.
13) Subject is a lactating or pregnant female.
14) Severe, active co-morbidity, defined as follows: ? Severe hepatic impairment (Child-Pugh category C or higher [score of 10 or higher; Subjects with mild or moderate hepatic impairment (Child-Pugh score of 5 - 9) may be eligible for treatment.? 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 21 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; ? Acute bacterial or fungal infection requiring intravenous antibiotics at the time of enrollment;
15) (14. continued) 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;
16) 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.
17) Inability to undergo contrast-enhanced MRI scans.
Information and next steps
Malignant neoplasms of eye brain and other parts of central nervous system
Phase II/Phase III
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