Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title 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)
IRB ABBV 2315
CC 16-1203
Hospital Main Campus
Phase Phase 2, Phase 3
Disease Brain, Glioblastoma
Drug ABT-414, Temozolomide
Description
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.
- 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
- 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)
- Change from baseline in neurocognitive functioning (HVLT-R and COWA)
- 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) 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) and PROs (EORTC QLQ-C30/BN 20, MDASI-BT)
- Change from maximum corticosteroid dosing
Inclusion Criteria
- Histologically confirmed de novo Grade IV glioma (GBM, gliosarcoma or other subvariants) confirmed by central pathology tissue screening.
- EGFR amplification in tumor tissue confirmed by central assessment.
- Supratentorial tumor.
- The subject must have recovered from the effects of surgery, post-operative 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.
- ≥ 18 years of age.
- Karnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomization (Step 2).
- Results for required stratification factors (EGFRvIII status, MGMT methylation status, Recursive Partitioning Analysis (RPA) class, and region of world) available prior to randomization (Step 2).
- Subject has adequate bone marrow, renal, and hepatic function ≤ 21 days prior to randomization (Step 2) as follows:
- Absolute neutrophil count (ANC) ≥1,500/mm3;
- Platelets ≥ 100,000/mm3;
- Hemoglobin (Hgb) ≥ 9.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dL is acceptable.);
- Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault formula;
- Hepatic function: Total bilirubin, Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) ≤ 1.5 times upper limit of normal (ULN). Subjects with Gilbert's syndrome documented in medical history may be enrolled if bilirubin is < 3 times ULN.
- Electrocardiogram (ECG) without evidence of acute cardiac ischemia ≤ 21 days prior to randomization (Step 2).
- 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) 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 treatment has ended. 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. In addition to the use of a condom, male subjects and their female partners of childbearing potential should practice at least one of the methods of birth control listed below during the 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.
- Women of child-bearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to randomization (Step 2).
- 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
- Subject has multifocal GBM.
- Gliomatosis cerebri (a diffuse glioma [usually astrocytic] growth pattern consisting of exceptionally extensive infiltration of a large region of the central nervous system [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.)
- Subject has recurrent GBM.
- Subject has infratentorial tumor.
- Subject has metastatic GBM.
- 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.
- Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields.
- Any prior therapy for glioblastoma (intra-operative techniques to guide resection are allowed as are experimental imaging techniques).
- 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.
- Prior, concomitant, or planned concomitant treatment with 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; the exceptions are diagnostic or imaging studies, quality of life, biomarker or epidemiological studies; and operative guides to improve extent of resection.
- Subject has had major immunologic reaction to an IgG-containing agent.
- Subject has had LASIK (laser-assisted in situ keratomileusis) procedure within the last 1 year or cataract surgery within the last 3 months.
- Subject has a history of hypersensitivity to TMZ or excipients, ABT-414 components or excipients, and dacarbazine (contraindication for TMZ).
- 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.
- Subject is a lactating or pregnant female.
- 16. Severe, active co-morbidity, defined as follows:
- Severe hepatic impairment (Child-Pugh category C or higher [score of 10 or higher (Appendix VII)]); Subjects with mild or moderate hepatic impairment (Child-Pugh score of 5 - 9) may be eligible for treatment, as described in Appendix IX.
- 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 (Appendix IV);
- 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;
- 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;
- 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.
- Inability to undergo contrast-enhanced MRI scans.