E7080 in Combination With Dacarbazine Versus Dacarbazine Alone as First Line Therapy in Patients With Stage IV Melanoma

• Safety Parameter: Adverse Events [ Time Frame: Until study termination; 3 years ] [ Designated as safety issue: Yes ]
  Phase 1B: To determine the MTD of E7080 in combination with dacarbazine as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7080. Phase II: Safety and tolerability of E7080 at the MTD determined in Phase Ib in combination with dacarbazine as measured by rate of adverse events by body system and grade.
• Concomitant Meds [ Time Frame: Until study termination; 3 years ] [ Designated as safety issue: Yes ]
  Phase 1B: To determine the MTD of E7080 in combination with dacarbazine as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7080. Phase II: Safety and tolerability of E7080 at the MTD determined in Phase Ib in combination with dacarbazine as measured by rate of adverse events by body system and grade.
• Lab Tests [ Time Frame: Day 1 and every 28 of every cycle until study terminaton; 3 years ] [ Designated as safety issue: Yes ]
  Phase 1B: To determine the MTD of E7080 in combination with dacarbazine as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7080. Phase II: Safety and tolerability of E7080 at the MTD determined in Phase Ib in combination with dacarbazine as measured by rate of adverse events by body system and grade.
• ECGs [ Time Frame: Day 1 and 30 days after termination of therapy; 3 years ] [ Designated as safety issue: Yes ]
  Phase 1B: To determine the MTD of E7080 in combination with dacarbazine as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7080. Phase II: Safety and tolerability of E7080 at the MTD determined in Phase Ib in combination with dacarbazine as measured by rate of adverse events by body system and grade.

• Efficacy Parameter [ Time Frame: Time Frame: Progression-Free Survival (PFS) Until disease progression or death for 3 years ] [ Designated as safety issue: No ]
  Phase 1B: To determine the MTD of E7080 in combination with dacarbazine as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7080. Phase II: Safety and tolerability of E7080 at the MTD determined in Phase Ib in combination with dacarbazine as measured by rate of adverse events by body system and grade.
• Efficacy Parameter [ Time Frame: Time Frame: Time to progression (TTP) Until disease progression or death for 3 years ] [ Designated as safety issue: No ]
  Phase 1B: To determine the MTD of E7080 in combination with dacarbazine as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7080. Phase II: Safety and tolerability of E7080 at the MTD determined in Phase Ib in combination with dacarbazine as measured by rate of adverse events by body system and grade.
• Efficacy Parameter [ Time Frame: Time Frame: Overall survival (OS) Until death for 3 years ] [ Designated as safety issue: No ]
  Phase 1B: To determine the MTD of E7080 in combination with dacarbazine as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7080. Phase II: Safety and tolerability of E7080 at the MTD determined in Phase Ib in combination with dacarbazine as measured by rate of adverse events by body system and grade.
• Efficacy Parameter [ Time Frame: Time Frame: Objective Response Rate (ORR) , Until termination of study drug or every 2 months up to 1 year during followup ] [ Designated as safety issue: No ]
  Objective Response Rate (ORR) , the number and percentage of patients with Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD)

Primary:

• Phase Ib: To define the safety, tolerability and maximum tolerated dose (MTD) of E7080 administered in combination with dacarbazine.
• Phase II: To evaluate the safety and tolerability of E7080 administered in combination with dacarbazine, compared with dacarbazine alone.

Secondary:

• Phase II: to make a preliminary assessment of the efficacy of E7080 administered in combination with dacarbazine, compared with dacarbazine alone.

• Drug: Dacarbazine
  Dacarbazine (1000 mg/m2) IV infusion over 60 minutes on Day 1 of a 21-day cycle.
  Other Name: DTIC-Dome
• Drug: E7080

  Test product: dose and mode of administration: E7080 will be provided as 1 mg, 4 mg, and 10 mg tablets. E7080 will be self-administered orally by patients, once-daily, over 3 weeks during each cycle. For the Phase Ib portion, the dose will be 16 mg, 20 mg, or 24 mg and for the Phase II portion, the dose will be the MTD as determined in the Phase Ib portion of the study.

  Number of cycles of E7080: until disease progression or unacceptable toxicity develops.

• Experimental: 2
  E7080
  Intervention: Drug: E7080
• Active Comparator: 1
  Dacarbazine
  Intervention: Drug: Dacarbazine

Inclusion Criteria:

• Patients may be entered in the study only if they meet all of the following criteria.

  1. Male or female patients greater than or equal to 18 years of age;
  2. Patients with histologically-confirmed metastatic melanoma (stage IV, AJCC);

  3. No prior cytokine, chemotherapy, or targeted therapy for Stage IV melanoma.

     • Patients who received adjuvant therapy must be at least 30 days from the last dose. Patients who received adjuvant vaccine therapy must be at least 6 months from the last dose.
     • Isolated limb perfusion therapy is not allowed. Prior resection for Stage III or Stage IV disease is allowed as long as the patient has unresectable lesions at the time of randomization.
  4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
  5. Life expectancy greater than or equal to 3 months;
  6. At least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1 version 1.1) criteria;

  7. Adequate hematologic, renal, liver, and coagulation system function as defined by laboratory values performed within 21 days prior to initiation of dosing.

     • Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L
     • Platelet count greater than or equal to 100 x 109/L
     • Hemoglobin greater than or equal to 9 g/dL
     • Serum creatinine less than or equal to 1.5 X ULN and/or creatinine clearance greater than or equal to 50 mL/min per the Cockcroft and Gault formula
     • Total serum bilirubin less than or equal to 1.5 X ULN
     • Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT) less than or equal to 2.5 X ULN, and less than or equal to 5 X ULN if liver metastases are present
     • PT/International normalized ratio (INR) less than or equal to 1.5 X ULN
     • PTT less than or equal to 1.1 X ULN
  8. Blood pressure must be well-controlled (less than or equal to 140/90 mmHg at screening) with or without antihypertensive medication. Patients must have no history of hypertensive crisis or hypertensive encephalopathy;
  9. Fertile men should use an effective method of contraception during treatment and for at least 3 months after completion of treatment as directed by their physician;
  10. Pre-menopausal women and women less than 2 years after the onset of menopause should have a negative pregnancy test at screening. Pre-menopausal women must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 90 days after the last dose of study drug. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for greater than or equal to 1 year;
  11. Before study entry, written informed consent must be obtained from patient prior to performing any study-related procedures.

Exclusion Criteria:

• Patients will not be entered in the study for any of the following reasons:

  1. Known CNS lesions, except for asymptomatic, nonprogressive, treated brain metastases. Treated brain metastases are defined as having no evidence of progression or hemorrhage, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Treatment for brain metastases must have been completed at least 4 weeks prior to Day 1 and may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Dexamethasone must be discontinued at least 3 weeks prior to Day 1. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded;
  2. Lactate dehydrogenase greater than or equal to 2.0 x ULN;
  3. Subjects with proteinuria greater than 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with 24-hour urine protein greater than or equal to 1 g/24 hours will be ineligible
  4. Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives or avoidance of pregnancy measures;
  5. Other active malignancy;
  6. History of or known carcinomatous meningitis;
  7. History of or known ocular melanoma;
  8. Are currently receiving any other treatment for the tumor (including palliative radiotherapy) aside from control of symptoms;
  9. Received treatment in another clinical study within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Grade less than or equal to 1, except for alopecia;
  10. Received radiotherapy within the 30 days prior to commencing study treatment or have not recovered from side effects of all radiation-related toxicities to Grade less than or equal to 1, except for alopecia;
  11. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 28 days prior to commencing study treatment. Minor surgery such as Portacath placement or skin biopsy is permitted if greater than or equal to 7 days have passed;
  12. History of bleeding diathesis or coagulopathy;
  13. Current use of anti-coagulants such as Vitamin K antagonists, unfractionated heparin, or low molecular weight heparin;
  14. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;
  15. Significant cardiovascular impairment (history of congestive heart failure greater than New York Heart Association [NYHA] Grade II [see Appendix 5]), unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
  16. Any history of cerebral vascular accident (CVA), transient ischemic attack (TIA), or greater than greater than or equal to Grade 2 peripheral vascular disease unless they have had no evidence of active disease for at least 6 months prior to randomization
  17. Active hemoptysis (defined as bright red blood of ½ teaspoon or more) within the 30 days prior to study entry;
  18. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the 6 months prior to enrolment;
  19. Patients with an allograft requiring immunosuppression;
  20. Known positive human immunodeficiency virus (HIV), known surface antigen positive for hepatitis B or hepatitis C positive;
  21. History of hypersensitivity reactions to dacarbazine or its excipients;
  22. Hypersensitivity to E7080 and/or E7080 chemical derivative; or
  23. Have any other uncontrolled infection or medical condition which would interfere with the conduct of the study.