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
Condition: Advanced Solid Tumors
MeSH terms: Neoplasms
Intervention: E7820; E7820
Intervention description: FOOD EFFECT STUDY:
Each subject (a minimum of 12 subjects) will be assigned according to a randomization code to receive a single 50 mg dose of E7820 on Day 1, either after fasting for 10 hours, or immediately after consuming a high fat breakfast. Following a 7-day washout period, the subjects will crossover and a second 50 mg dose of E7820 will be administered on Day 8.; MTD DETERMINATION FOR BID DOSING SCHEDULE
The initial dose of E7820 will be 50 mg BID. If allowed by the rules for dose escalation, the dose escalations will be to 60 mg BID, 80 mg BID, and 100 mg BID.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 45.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study consists of two Parts. Part A (Food Effect Study) and Part B (Determination of
      Maximum Tolerated Dose [MTD] for twice daily [BID] Dosing).Part A will be initiated first,
      and Part B will be initiated after the PK results of Part A have been evaluated.
    

Eligibility criteria:

        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 less than or equal to 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 less than or equal to 1.5 times the
             upper limits of normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT),
             and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of
             liver metastases less than or equal to 5 x ULN) In case alkaline phosphatase is
             greater than 3 x ULN (in absence of liver metastases) or greater than 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 less than or equal to 2.0
             mg/dL (177 micro-mol/L) or calculated creatinine clearance greater than or equal to 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) greater
             than or equal to 1.5 x 109/L, hemoglobin greater than or equal to 9 g/dL (5.5 mmol/L)
             and platelet count greater than or equal to 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 [beta-hCG] test with a minimum sensitivity
             of 25 IU/L or equivalent units of beta-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.

        Exclusion Criteria:

          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 greater than or equal 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 less than 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 less than 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 greater than 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 (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.