Phase II Trial Of ZK-EPO (ZK 219477) In Metastatic Melanoma

• Number of Participants With Overall Survival (OS) [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
  To determine the time to progression and overall survival of patients treated with ZK-Epo
• Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
  To evaluate the toxicity profile of ZK-Epo in this patient population
• Participants' Pharmacokinetic Parameters [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
  To determine pharmacokinetic parameters of ZK-Epo as administered

• To determine the time to progression and overall survival of patients treated with ZK-Epo [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
• To evaluate the toxicity profile of ZK-Epo in this patient population [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
• To determine pharmacokinetic parameters of ZK-Epo as administered [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]

The purpose of this study is to find out how effective an investigational drug named ZK-Epo is against melanoma. Although ZK-Epo has been studied in the treatment of cancer, it is not approved for use in treating melanoma. This research is being done because currently there are only a limited number of treatment options for patients who have melanoma that has spread to distant organs.

We expect each patient to be in this study for at least 2 cycles. One cycle lasts for 21 days. If their tumor does not grow after 2 cycles and they do not have any major side-effects, they may receive up to 6 cycles of ZK-Epo.

If after they have received 6 cycles of ZK-Epo and their doctor determines that the tumor is continuing to shrink, they will continue treatment with ZK-Epo. The number of treatments the patient receives after 6 cycles will depend upon when their doctor feels there has been maximum tumor response (tumor shrinkage). Two treatments will be given beyond what their doctor considers the point of maximum shrinkage. We estimate that they will spend anywhere from 1 1/2 months to 5 months taking part in this study.

Each Cycle is a 21 day period. On the first day of each cycle each patient will receive the study drug, ZK-Epo, through an IV infusion over a 3 hour period. Patients will receive the study drug only once every 21 day period.

At the start of each cycle patients will have the following tests:

• Patients will be asked questions about their medical history and health and undergo a complete physical exam.
• Blood tests will be done to check blood cell count and organ functions (about 1 tablespoon of blood will be taken).
• Performance status tests (will determine patient's ability to perform everyday functions).
• A nurse or doctor will ask patients how they are feeling and about any side effects that patients may be having.
• Pre Study Visit: Blood test called lactate dehydrogenase (LDH) to check organ function. Prothrombin time (PT) and an a partial thromboplastin time (PTT) to see if the patient's blood clots normally. Electrocardiogram (EKG) (to measure the electrical function of patient's heart). Pregnancy Test (IF APPLICABLE a woman of child bearing age). Optional Tumor Biopsy (If indicated by patient's physician).
• Cycle 1, Day 1: Pharmacokinetics: special blood tests to measure the drug levels, LDH
• Cycle 1, Day 2 & 8: Pharmacokinetics
• Cycle 1, Day 15: EKG
• Cycle 2, DAY 1: LDH
• Cycle 3, DAY 1: LDH, PT & activated partial thromboplastin time (aPTT)
• Cycle 4, 5, & 6, and all subsequent cycles, Day 1: LDH

During the first cycle only patients will also need to come for a study visit on day 8 and 15. During these two visits, blood tests will be done again to check blood cell count and organ functions. Patients will also be asked how they are feeling and about any side effects that they may be having.

Computed tomography (CT) scans or a magnetic resonance imaging (MRI) will be done after every 2 cycles that each patient completes on the study. These will be done to help the doctor re-evaluate each patient's disease.

Patients may have some additional blood tests done if they are among the first 10 patients taking part in this study. In this case they will have 9 samples of blood (each about a teaspoonful) drawn from them at specifically timed intervals (at 30 minutes before the start and at 30 minutes, 2 hour 55 minutes, 3 hour 10 minutes, 3 hour 30 minutes, 5 hour, 8 hour, 27 hour (+/- 1 hour) and 168 hour (+/- 4 hours) after the start of the ZK-Epo infusion) so that we can better understand the level of this drug in the body and its metabolism in people.

Inclusion Criteria:

• Histologically or cytologically confirmed Malignant Melanoma.
• Unresectable Stage III or Stage IV disease.
• At least 1 measurable lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Adequate function of major organs and systems as measured by the following criteria:

Bone Marrow:

• Hemoglobin ≥ 10 g/dL
• White blood count (WBC) ≥ 3,000/mm^3
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic:

• Bilirubin within 1.5 times normal limit
• aspartate transaminase (AST)/Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal (ULN)

Renal:

• Creatinine ≤ 2 mg/dL

Cardiovascular:

• No New York Heart Association (NYHA) class III or IV Congestive heart failure
• No unstable angina pectoris
• No arrhythmia needing continuous treatment

Nervous system:

• No Grade ≥ 2 peripheral neuropathy

Exclusion Criteria:

• More than 2 previous chemotherapy regimens.
• Any prior treatment with Epothilones, Epothilone analogues, taxanes, or vinca alkaloids.
• Any progressive central nervous system (CNS) metastatic disease. Patients with CNS metastases may be allowed if stable for 8 weeks or more and patient is neurologically intact and off of steroids. The stability must be documented by MRI/CT over a period of 8 weeks or greater.
• Any radiotherapy, chemotherapy, or immunotherapy within 3 weeks prior to first dose of ZK-Epo. If patients were previously on temozolomide with extended dose schedule, they must be off 1 week prior to the first dose of ZK-Epo.