An Open-label, Dose Escalation, Pharmacodynamic, Pharmacokinetic, and Effect of Food Phase 1 Study of E7820, to Determine the Maximum Tolerated Dose Following Twice Daily Oral Administration in Subjects With Unresectable Solid Tumors
1. Age 18 years or older.
2. Histological or cytological evidence of an unresectable or refractory solid tumor.
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
4. Subjects with known brain metastases will be eligible under the following conditions
A. Have undergone complete surgical excision and are more then 1 month post surgery
with no radiographic evidence of brain disease recurrence or B. Have undergone
stereotactic radio surgery (gamma knife procedure) and are more then 1 month post
procedure and with no radiographic evidence of brain disease progression and C. Are
asymptomatic and D. Discontinued corticosteroid treatment at least 30 days prior to
Cycle 1, Day 1
5. Adequate liver function as evidenced by bilirubin ≤ 1.5 times the upper limits of
normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN) In case
alkaline phosphatase is > 3 x ULN (in absence of liver metastases) or > 5 x ULN (in
presence of liver metastases) AND subject also is known to have bone metastases, the
liver specific alkaline phosphatase must be separated from the total and used to
assess the liver function instead of the total alkaline phosphatase.
6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 mg/dL (177 μmol/L) or
calculated creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula
7. Provide written informed consent.
8. Are willing and able to comply with all aspects of the protocol.
9. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x
109/L, hemoglobin ≥ 9 g/dL (5.5 mmol/L) and platelet count
≥ 100 x 109/L.
10. Females must not be lactating or pregnant at Screening or Baseline (as documented by
a negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity
of 25 IU/L or equivalent units of ß-hCG). A separate baseline assessment is required
if a negative screening pregnancy test was obtained more than 72 hours before the
first dose of study drug.
11. All females will be considered to be of childbearing potential unless they are
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate
age group, and without other known or suspected cause) or have been sterilized
surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral
oophorectomy, all with surgery at least 1 month before dosing).
12. Females of childbearing potential must not have had unprotected sexual intercourse
within 30 days prior to study entry and must agree to use a highly effective method
of contraception (e.g., total abstinence, an intrauterine device, a double-barrier
method [such as condom plus diaphragm with spermicide], a contraceptive implant, an
oral contraceptive or have a vasectomized partner with confirmed azoospermia)
throughout the entire study period and for 30 days after study drug discontinuation.
If currently abstinent, the subject must agree to use a double-barrier method as
described above if she becomes sexually active during the study period or for 30 days
after study drug discontinuation. Females 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.
13. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they
and their female partners must meet the criteria above (i.e., not of childbearing
potential or practicing highly effective contraception throughout the study period
and for 30 days after study drug discontinuation). No sperm donation is allowed
during the study period and for 30 days after study drug discontinuation.
1. Leptomeningeal metastases or brain metastases (except as for inclusion criteria #4).
2. Active hemoptysis (at least 2.5 mL [0.5 teaspoon] bright red blood) within 3 weeks
prior to the first dose of study drug.
3. Hypersensitivity to sulfonamide derivatives.
4. Subjects who have had radiation to ≥ 30% of their bone marrow.
5. Subjects who require therapeutic anti-coagulant therapy with warfarin or related
vitamin K antagonists. Prophylactic doses of heparin or low molecular weight heparin
or thrombin inhibitors may be used in place of warfarin.
6. Left ventricular ejection fraction < 50% on echocardiography or MUGA scanning.
7. Anticancer therapies that have not been completed at least 28 days (42 days in the
case of mitomycin C or nitrosoureas) prior to treatment with E7820 (other than
surgery or treatment with a protein kinase inhibitor which must have been completed
no less than one week prior to treatment with E7820).
8. Incomplete recovery from previous radiotherapy, chemotherapy, or surgery other than
residual cutaneous effects or stable < Grade 2 gastrointestinal toxicity.
9. History of an ischemic cardiac event, myocardial infarction or unstable cardiac
disease within 3 months before study entry.
10. A clinically significant electrocardiogram (ECG) abnormality, including a marked
baseline prolongation of QTc interval > 480 msec.
11. Evidence of clinically significant disease (e.g., cardiac, respiratory,
gastrointestinal, renal disease) that in the opinion of the investigator(s) could
affect the subject's safety or study conduct.
12. Concurrent treatment with CYP3A4 inhibitors such as verapamil, cyclosporin,
quinidine, erythromycin, mibefradil, clarithramycin and azoles.
13. Concurrent treatment with drugs known to be extensively metabolized by CYP2C9 and/or
14. Chronic treatment with known inducers of CYP3A4 within four weeks of receiving
treatment with E7820 other than corticosteroids (Appendix 6).
15. Subjects who have a positive test result for human immunodeficiency virus (HIV),
hepatitis A, hepatitis B or hepatitis C.
16. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
17. History of drug or alcohol dependency or abuse within approximately the last 2 years.
18. Presence of a progressive central nervous system (CNS) disease, including
degenerative CNS diseases and progressive tumors.
19. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring
active treatment, including the use of oxygen.
20. Use of illegal recreational drugs.
21. Any medical or other condition that, in the opinion of the investigator, would
preclude the subject's participation in a study.