E7050 in Combination With E7080 in Subjects With Advanced Solid Tumors (Dose Escalation) and in Subjects With Recurrent Glioblastoma or Unresectable Stage III or Stage IV Melanoma After Prior Systemic Therapy (Expansion Cohort and Phase 2)

Inclusion Criteria

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

1. Phase 1b: Unresectable advanced or metastatic solid tumors.

2. Phase 1b expansion cohort and Phase 2: Histological confirmed diagnosis of
glioblastoma (expansion cohort and Cohort 1) or melanoma (expansion cohort and Cohort
2).

Phase 1b expansion cohort glioblastoma subjects, Phase 2 Cohort 1:

3. No evidence of active CNS hemorrhage on baseline scans other than in those subjects
with recurrent glioblastoma who are stable Grade 1.

4. Subjects having first or second recurrence documented by magnetic resonance imaging
(MRI), following primary management with surgical resection or biopsy, radiotherapy
and up to two prior systemic treatments.

5. If subject is on corticosteroids, they must be on a stable dose for 1 week prior to
first dose of study drug.

6. Measurable disease defined as bidimensionally contrast enhancing lesions with clearly
defined margins by computerized tomography (CT) or MRI scan, with a minimal diameter
of 1 cm, and visible on two axial slices which are preferably at most 5 mm apart with
0 mm skip.

Phase 1b expansion cohort melanoma subjects, Phase 2 Cohort 2:

7. Radiographic/ photographic evidence of disease progression according to Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) (Appendix 3) after no more than two
prior systemic regimens for unresectable Stage III or Stage IV disease.

8. American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV
melanoma.

9. Measurable disease meeting the following criteria:

1. At least one lesion of greater than or equal to 1.0 cm in the longest diameter
for a non-lymph node or greater than or equal to 1.5 cm in the short-axis
diameter for a lymph node which is serially measurable according to RECIST 1.1
using CT/MRI or photography. If there is only one target lesion and it is a
non-lymph node, it should have a longest diameter of greater than or equal to
1.5 cm.

2. Lesions that have had external beam radiotherapy or loco-regional therapies such
as radiofrequency ablation must show evidence of progressive disease based on
RECIST 1.1 to be deemed a target lesion.

All subjects:

10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

11. Adequately controlled BP with or without antihypertensive medications, defined as BP
less than or equal to 150/90 mmHg at screening and no change in antihypertensive
medications within 1 week before the Screening Visit.

12. Adequate renal function as evidenced by serum creatinine less than or equal to 2.0
mg/dL or calculated creatinine clearance greater than or equal to 40 mL/min per the
Cockcroft and Gault formula (see Appendix 5).

13. Adequate bone marrow function:

- Absolute neutrophil count greater than or equal to 1500/mm3 (greater than or
equal to 1.5 x 10^3/uL);

- Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 x
10^9/L);

- Hemoglobin greater than or equal to 9.0 g/dL.

14. Adequate blood coagulation function, as evidenced by an International Normalized
Ratio (INR) less than or equal to 1.5.

15. Adequate liver function:

- Bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) except for
unconjugated hyperbilirubinemia of Gilbert's syndrome;

- ALP, ALT, and AST less than or equal to 3 x ULN (less than or equal to 5 x ULN
if subject has liver metastases).

16. Males or females age greater than or equal to 18 years at the time of informed
consent.

17. All females must have a negative serum or urine pregnancy test (minimum sensitivity
25 IU/L or equivalent units of beta-human chorionic gonadotropin [B-hCG] at the
Screening and Baseline Visit (a separate Baseline assessment is not required if a
negative Screening pregnancy test was obtained within 72 hours before the first dose
of study drug). Females of child-bearing potential, if not practising total
abstinence or having a vasectomized partner with confirmed azoospermia, must agree to
use two highly effective methods of contraception: e.g., 1) an intrauterine device
(IUD) or intrauterine system (IUS); 2) a barrier method such as a condom or occlusive
cup (diaphragm or cervical/vault caps) + spermicide (foam, gel, cream, etc.); 3)
oral, injected, or implanted hormonal contraceptives throughout the entire study
period and for 30 days after study drug discontinuation. Use of a double-barrier
method (i.e., use at the same time of a condom + occlusive cup [diaphragm or
cervical/vault caps] + spermicide [foam, gel, cream, etc.]) is accepted as two highly
effective methods of contraception. 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 (i.e., bilateral tubal ligation with surgery at least 1
month prior to dosing, total 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.

18. Male subjects who are partners of women of childbearing potential must use a condom +
spermicide and their female partners, if of childbearing potential, must use a highly
effective method of contraception (see methods described in Inclusion Criterion #18)
beginning at least 1 menstrual cycle prior to starting study drug, throughout the
entire study period, and for 30 days after the last dose of study drug, unless the
male subjects are totally abstinent sexually or have undergone a successful vasectomy
with confirmed azoospermia or unless the female partners have been sterilized
surgically or are otherwise proven sterile (see Inclusion Criterion #18).

19. 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. Phase 1b Dose Escalation: Subjects who discontinued prior TK inhibitor (including
VEGFR and c-Met receptor targeted therapy) due to toxicity will be ineligible.

2. Phase 1b Dose Escalation (3+3 portion) subjects with primary CNS tumors

3. Phase 1b Dose Escalation subjects, melanoma subjects in expansion cohort and Phase 2
Cohort 2: Subjects with untreated or unstable metastases to the central nervous
system (CNS) are excluded. Subjects who have completed local therapy and have
discontinued the use of steroids for this indication at least 4 weeks prior to
commencing treatment and have remained asymptomatic for at least 4 weeks prior to
commencing treatment are eligible.

4. Phase 2: Prior exposure to VEGF-targeted treatment or c-Met or hepatocyte growth
factor (HGF) targeted treatment.

5. Phase 2: Active malignancy (except for glioblastoma (Cohort 1) or unresectable Stage
III or Stage IV melanoma (Cohort 2); or melanoma in situ, basal or squamous cell
carcinoma of the skin, or carcinoma in situ of the cervix) within the past 24 months.

Phase 1b expansion cohort glioblastoma subjects and Phase 2 Cohort 1:

6. More than two recurrences of glioblastoma.

7. Prior bevacizumab treatment.

8. Surgical resection of brain tumor within 4 weeks, or prior stereotactic biopsy within
2 weeks of Screening visit.

9. 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
histopathology sampling (e.g., "solid" tumor areas (i.e. greater than 70% tumor cell
nuclei in areas), high or progressive increase in MIB-1 proliferation index compared
to prior biopsy, or evidence for histological progression or increased anaplasia in
the tumor).

10. Subjects who have received enzyme-inducing anti epileptic agents within 14 days
before the first dose of study drug (e.g., carbamazepine, phenytoin, phenobarbital,
primidone, or oxcarbazepine).

Phase 1b expansion cohort subjects with melanoma and Phase 2 Cohort 2:

11. More than two prior systemic regimens for unresectable Stage III or Stage IV disease.

All subjects:

12. Prior exposure to E7050 or lenvatinib.

13. Melanoma of intraocular origin.

14. Subjects who have received any anticancer treatment within 21 days (6 weeks for
nitrosureas Cohort 1) or any investigational agent within 30 days prior to the first
dose of study drug or who have not recovered from any acute toxicity related to
previous anticancer treatment.

15. Major surgery within 3 weeks prior to the first dose of study drug.

16. Subjects having greater than 1+ proteinuria on urinalysis will undergo 24-hour urine
collection for quantitative assessment of proteinuria. Subjects with urine protein
greater than or equal to 1 g/24-hour will be ineligible.

17. Inability to take oral medication, gastrointestinal malabsorption, gastrointestinal
anastomosis, or any other condition that might affect the absorption of E7050 or
lenvatinib.

18. 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.

19. Prolongation of QTc interval to greater than 480 msec.

20. Bleeding disorder or thrombotic disorder requiring anticoagulant therapy, such as
warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low
molecular weight heparin [LMWH] is allowed).

21. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to
the first dose of study drug.

22. Active infection (any infection requiring antibiotics).

23. Known intolerance or known hypersensitivity to any of the study drugs (or any of the
excipients).

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

25. Females who are pregnant or breastfeeding.