Study to Assess the Tolerability of a Bispecific Targeted Biologic IMCgp100 in Malignant Melanoma

Inclusion Criteria:

1. Pathologically documented Stage IV malignant melanoma or unresectable Stage III melanoma for which no standard effective therapy exists or for which an appropriate window exists between alternative therapeutic options. Patients for whom early treatment with vemurafenib is indicated e.g. rapidly progressing or symptomatic disease, are excluded from this trial.
2. Previous surgery (other than resection of skin metastases), radiotherapy, chemotherapy, immunotherapy or experimental therapy completed >4 weeks before and all adverse events resolved to ≤ grade 1. In cases where localised radiotherapy has been applied, treatment with IMCgp100 can be commenced after a two week period.
3. HLA A2 positive.
4. ≥ 18 years old.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
6. For patients in the Dose-Expansion part only, measurable disease according to RECIST criteria. For patients in the Dose-escalation part of the study, only 'assessable disease' is required.
7. Life expectancy >3 months.

8. Blood tests within the following parameters:

   1. Platelet count ≥100 x 109/L
   2. Haemoglobin ≥10g/dL
   3. Calculated creatinine clearance ≥60 mL/min using the modified Cockcroft-Gault equation
   4. Neutrophil counts ≥1x109/L
   5. Lymphocyte count ≥0.5x109/L
9. Female patients of childbearing potential must use maximally effective birth control during the period of therapy, must be willing to use contraception for 6 months following the last study drug infusion and must have a negative urine or serum pregnancy test upon entry into this study. Otherwise, female patients must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile.
10. Male patients must be surgically sterile or willing to use a double barrier contraception method upon enrolment, during the course of the study, and for 6 months following the last study drug infusion.
11. Able to give informed consent.

Exclusion Criteria:

1. Symptomatic brain metastases that are unstable, require steroids, or that have required radiation within the last 28 days
2. Other active malignancy in the past 5 years except carcinoma in situ, completely excised non-melanomatous skin cancer or any other malignancy that in the opinion of the investigator is considered to be cured.
3. Comorbid medical condition that would increase the risk of toxicity in the opinion of the investigator or sponsor. Any symptomatic ongoing infection must be resolved before the patient can be treated in the study.
4. Uveitis
5. Had myocardial infarction within 1 year before enrolment, symptomatic congestive heart failure (New York Heart Association >Class II), unstable angina or unstable cardiac arrhythmia requiring medication.
6. Has an ejection fraction <50%.
7. Clinically significant electrocardiogram (ECG) changes that obscure the ability to assess the RR, PR and QT intervals. Patients with QTc calculated by Bazetts or locally preferred formula which is greater than 500ms.

8. Has hepatic function as follows:

   1. Aspartate aminotransferase >2.5 x upper limit of normal (ULN)
   2. Alanine aminotransferase >2.5 x ULN
   3. Bilirubin >2.0 x ULN
   4. Prothrombin time or partial thromboplastin time>1.5 x ULN
9. Bleeding diathesis.
10. Immunosuppressive condition or treatment including previous transplantation, splenectomy or known HIV infection.
11. Has a history of adult seizures.