An Open-label, Dose Escalation, Pharmacodynamic, Pharmacokinetic, and Effect of Food Phase 1 Study of E7820, Administered as a Once Daily and Twice Daily Oral Dose to Determine the Maximum Tolerated Dose in Subjects with Unresectable Solid Tumors

Completed

Conditions: Solid Tumors
10027655

Registration Number: NL-OMON36618

Lead Sponsor: Eisai

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 24

Inclusion Criteria

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. 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 phosphatise must be separated from the total and used to assess the liver function instead of the total alkaline phosphatise.
5. 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.
6. Provide written informed consent.
7. Are willing and able to comply with all aspects of the protocol.
8. 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.
9. All females must have a negative serum ß-hCG test result or a negative urine pregnancy test results at Screening and Baseline. Females of child-bearing potential must agree to use a medically acceptable method of contraception (e.g., abstinence, an intrauterine device [IUD], a highly effective method of contraception 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 greater than age 50 and at least 12 months of amenorrhea) or subjects who have been sterilized surgically (i.e., as a result of tubal ligation, hysterectomy or bilateral oophorectomy) or who are otherwise proven sterile. 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.
10. Male subjects who are partners of women of childbearing potential must use or their partners must use a highly effective method of contraception (e.g., condom + spermicide, condom + diaphragm with spermicide, an 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).
Additional Inclusion Criterion Specific for Part B and C Expansion Cohorts Only
11. Subjects must have at least one metastatic lesion, EITHER >= 3 cm in the lung or liver OR a lesion >=2 cm in other parts of the body that are less subject to motion with breathing. The existence of an appropriately sized lesion should be determined on the basis of the pretreatment CT scan.

Exclusion Criteria

1. Central nervous system metastases.
2. Hemoptysis.
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 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 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 CYP2C19
14. Chronic treatment with known inducers of CYP3A4 within four weeks of receiving treatment with E7820 other than corticosteroids.
15. Subjects who have a positive test result for human immunodeficiency virus (HIV), hepatitis A, hepatitis B or hepatitis C.
16. Suffering from psychotic disorder(s) and/or unstable recurrent affective disorder(s) evident by use of antipsychotics or have had a 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. Subjects with meningeal carcinomatosis.
20. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
21. Use of recreational drugs.
22. Any history of or concomitant medical condition that, in the opinion of the Investigator, would compromise the subject*s ability to safely complete the study
Additional Exclusion Criteria Specific for Parts B and C Expansion Cohorts
Subjects enrolled in the Expansion Cohort of Parts B and C of the study are excluded from DCE-MRI/DWI-MRI procedures for the following reasons:
1. Cardiac pacemaker
2. Ferromagnetic metal implants other than those approved as safe for use in MRI scanners (e.g., aneurysm clips, shrapnel)
3. Obesity exceeding equipment limits
4. Inability to tolerate DCE-MRI/DWI-MRI scanning procedure
5. History of severe allergic reaction to MR contrast agent

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Part A: Determination of effect of food on disposition of E7820<br /><br>Part B: Determination of MTD for once-daily dosing<br /><br>Part C: Determination of MTD for twice-daily dosing </p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Determination of the safety and tolerability of E7820 administered QD.<br /><br>Determination of the pharmacokinetics of E7820 administered<br /><br>Assessment of evidence of efficacy by RECIST 1.1 </p><br>