Phase 1 Study of the Poly (ADP-Ribose) Polymerase Inhibitor E7016 in Combination With Temozolomide in Subjects With Advanced Solid Tumors

Inclusion Criteria:

Subjects who meet all of the following criteria may be included in the study.

1. Histopathologically confirmed melanoma or other solid tumors (excluding malignant
brain tumors) for which no standard therapy is available (Dose-Escalation Component
only). During the Expansion Component, enrollment will be restricted to subjects with
histopathologically proven gliomas and will include subjects eligible for TMZ therapy
as well as those who have failed TMZ therapy; and those who are either not
appropriate candidates for radiation therapy or who refuse radiation therapy.
Subjects who are taking either strong cytochrome P450 (CYP) inhibitors or inducers
may be enrolled.

2. Life expectancy greater than or equal to 3 months after starting E7016.

3. Performance status (PS) 1 to 2 on the Eastern Cooperative Oncology Group (ECOG)
scale.

4. Adequate renal function indicated by serum creatinine less than 1.5 mg/dL or
calculated creatinine clearance greater than 50 mL/minute.

5. Adequate bone marrow reserve:

1. ANC greater than or equal to 1500/mm3,

2. Platelets greater than or equal to 100,000/mm3 (without transfusion),

3. Hemoglobin greater than or equal to 10 g/dL (less than 10.0 g/dL is acceptable
if corrected by growth factor or transfusion).

6. Adequate liver function:

1. Bilirubin less than or equal to 1.5x the upper limit of normal (ULN) (less than
or equal to 3 x ULN if subject has liver metastases),

2. Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) less than or equal to 3 times ULN (less than or equal to
5 x ULN if subject has liver metastases).

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

1. Female subjects of childbearing potential must have a negative serum beta human
chorionic gonadotropin (BhCG) test at Visit 1 (Screening) and a negative urine
pregnancy test prior to the first dose of E7016 capsules in the Single-Dose PK
Period and again prior to the first dose of E7016 in Cycle 1.

2. 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, 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.

Exclusion Criteria:

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

1. Subjects with primary or metastatic brain tumors are excluded from the
Dose-Escalation Component.

2. Subjects with active malignancies other than gliomas are excluded from the Expansion
Component.

3. Subjects taking medications which are either strong CYP inhibitors or inducers will
be excluded from the Dose-Escalation Component.

4. Prior treatment with a PARP inhibitor.

5. Inability to tolerate 150 mg/m2/d TMZ during previous therapy with TMZ.

6. Known allergy, hypersensitivity, or other contraindication to E7016, TMZ, or
dacarbazine or any of the other components of the formulations.

7. Known human immunodeficiency virus infection, active hepatitis B or C.

8. Active infections requiring specific anti-infective therapy

9. Subjects who have had a major surgical procedure (including tumor resection) within 4
weeks prior to initiating E7016 treatment.

10. Subjects scheduled for surgery during the projected course of the study.

11. Females who are pregnant (positive B-hCG test) or breastfeeding.

12. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to initiating
E7016 treatment (6 weeks for mitomycin C or nitrosoureas).

13. Prolongation of QTc interval (500 msec).

14. Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to
raise gastric pH within 2 weeks prior to study drug administration.

15. Any history of or concomitant medical condition or clinically significant disease
making the subject medically unfit to receive the study drug or, in the opinion of
the investigator, unsuitable for any other reason.

16. Unable to swallow multiple capsules.

17. History of drug or alcohol dependency or abuse within approximately the last 2 years.