A Study in Subjects With Recurrent Malignant Glioma

Inclusion Criteria

Subjects must meet all of the following criteria to be included in this study:

1. Histologically confirmed diagnosis of grade 3 or 4 malignant glioma.

2. 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.

3. Karnofsky score of 70% or greater

4. 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.

5. Adequate renal function, defined as a calculated creatinine clearance ≥ 30 mL/min per
the Cockcroft and Gault formula.

6. 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.

7. Adequate blood coagulation function as evidenced by an International Normalized Ratio
(INR) ≤ 1.5.

8. 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.

9. No evidence of hemorrhage on the baseline MRI scan other than in those subjects who
are stable grade 1.

10. Males or females age ≥ 18 years at the time of informed consent.

11. 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.

12. 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.

13. Voluntary agreement to provide written informed consent and the willingness and
ability to comply with all aspects of the protocol.

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from this study:

1. Females who are pregnant or breastfeeding.

2. 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).

3. Active infection requiring intravenous antibiotics.

4. Therapeutic anti-coagulation with warfarin, aspirin, nonsteroidal anti-inflammatory
drugs or clopidogrel (low molecular weight heparin is acceptable).

5. 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.

6. Prior surgical resection within 4 weeks, or prior stereotactic biopsy within 2 weeks,
of Screening Visit.

7. 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).

8. 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.

9. Gastrointestinal anastomosis, or any other condition that might affect the absorption
of E7080.

10. 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.

11. Prolongation of QTc interval to > 480 msec.

12. Active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to
the first dose of study drug.

13. 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.

14. Known intolerance to any of the study drugs (or any of the excipients).

15. Any medical or other condition which, in the opinion of the investigator, would
preclude participation in a clinical trial.

16. Inability to swallow and retain oral medication.