- Drug: E7080
Will assess subjects with recurrent GBM who are bevacizumab-naïve. Approximately 98 subjects accrued in Cohort 1 will be randomized in a 1:1 ratio to receive 24 mg E7080 (Arm A), orally once daily or bevacizumab (Arm B) at a dose of 10 mg/kg intravenously every 2 weeks in 28-day cycles. A subject in Cohort 1 with disease progression following bevacizumab treatment may be enrolled in Cohort 3. The subject must be assigned a new Subject Identification Number.
- Drug: E7080
Will assess subjects with recurrent grade 3 malignant glioma who are bevacizumab-naïve. Approximately 40 subjects in Cohort 2 will be treated with 24 mg E7080 orally, once daily in 28-day cycles.
- Drug: E7080
Will assess subjects with recurrent GBM who have disease progression following prior bevacizumab treatment. Approximately 32 subjects will receive 24 mg E7080 orally, once daily in 28-day cycles in Cohort 3. Treatment will continue until disease progression, development of unacceptable toxicity, withdrawal of consent, or discontinuation of E7080 development by the Sponsor. The primary endpoint of each cohort is 6-month progression-free survival rate. The assessment will be made separately among the 3 cohorts.
Subjects must meet all of the following criteria to be included in this study:
- Histologically confirmed diagnosis of grade 3 or 4 malignant glioma.
All subjects who have a first or second recurrence following primary management with surgical resection or biopsy, radiotherapy and up to 2 prior systemic treatments with addition of:
- No prior bevacizumab treatment is allowed for Cohort 1 and Cohort 2.
- Subjects must have disease progression following prior bevacizumab treatment for Cohort 3.
- Karnofsky score of 70% or greater
- Adequately controlled blood pressure with or without antihypertensive medications, defined as BP < 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.
- Adequate renal function, defined as a calculated creatinine clearance ≥ 30 mL/min per the Cockcroft and Gault formula.
Adequate bone marrow function defined by following:
- absolute neutrophil count (ANC) ≥ 1000/mm3 (≥ 1.0 x 103/μL)
- platelets ≥ 100,000/mm3 (≥ 100 x 109/L)
- hemoglobin ≥ 9.0 g/dL.
- Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5.
Adequate liver function defined by following criteria:
- bilirubin ≤ 1.5 x ULN except for unconjugated hyperbilirubinaemia of Gilbert's syndrome,
- alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) each ≤ 3 x ULN.
- No evidence of hemorrhage on the baseline MRI scan other than in those subjects who are stable grade 1.
- Males or females age ≥ 18 years at the time of informed consent.
- All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [β-hCG] at the Screening Visit and/or within 48 hours of the first dose of study drug). Females of child-bearing potential must agree to use a medically acceptable method of contraception (eg, abstinence, an intrauterine device, a double-barrier method such as condom + spermicide or condom + diaphragm with spermicide, a contraceptive implant, an oral contraceptive or have a vasectomised partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (ie, bilateral tubal ligation with surgery at least 1 month prior to dosing, hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to dosing). All women who are of reproductive potential and who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
- Male subjects who are partners of women of childbearing potential must use, or their partners must use, a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, intrauterine device (IUD) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 30 days after the last dose of study drug, unless they are sexually abstinent or have undergone a successful vasectomy. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception, as described previously.
- Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
Subjects who meet any of the following criteria will be excluded from this study:
- Females who are pregnant or breastfeeding.
- Subjects who have received enzyme-inducing anti-epileptic agents within 14 days before the first dose of study drug (eg, carbamazepine, phenytoin, Phenobarbital, primidone, or oxcarbazepine).
- Active infection requiring intravenous antibiotics.
- Therapeutic anti-coagulation with warfarin, aspirin, nonsteroidal anti-inflammatory drugs or clopidogrel (low molecular weight heparin is acceptable).
- Subjects having > +1 proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with 24-hour urine protein ≥ 1 gm will be ineligible.
- Prior surgical resection within 4 weeks, or prior stereotactic biopsy within 2 weeks, of Screening Visit.
- Prior radiotherapy within 12 weeks unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field (beyond the high dose region or 80% isodose line), or there is biopsy-proven unequivocal viable tumor on histopathologic sampling (e.g. "solid" tumor areas (i.e. >70% tumor cell nuclei in areas), high or progressive increase in MIB-1 proliferation index compared to prior biopsy, or evidence for histologic progression or increased anaplasia in tumor).
- Prior chemotherapy (6 weeks for nitrosoureas), or any investigational agent within 4 weeks unless the subject has recovered from all anticipated toxicities associated with that therapy; prior bevacizumab therapy (Cohorts 1 and 2); for Cohort 3, prior bevacizumab therapy within 3 weeks.
- Gastrointestinal anastomosis, or any other condition that might affect the absorption of E7080.
- Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II ; unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment.
- Prolongation of QTc interval to > 480 msec.
- Active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to the first dose of study drug.
- Active malignancy (except for grade 3 or 4 malignant glioma, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
- Known intolerance to any of the study drugs (or any of the excipients).
- Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.
- Inability to swallow and retain oral medication.