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

IMCgp100 is a bispecific biologic incorporating an engineered T cell receptor (TCR) specific
for a peptide antigen derived from the protein gp100 presented in the context of HLA A2 on
the surface of melanoma cells. The TCR is fused to an anti-CD3 antibody single-chain
variable fragment (scFv) that recruits and activates non-melanoma specific T cells (killer T
cells) in physical contact with the cancer T cell. This is a Phase I study designed to
assess the safety profile and establish a tolerable dose of IMCgp100 in HLA A2 positive
malignant melanoma patients. The study has two treatment arms with different treatment
schedules, weekly or daily dosing. Each treatment arm in the study has two parts. In the
first part, dose escalation, the safety and tolerability of the drug are examined and the
optimal dose of drug is established. In the second part of the trial, patients will receive
an extended course of treatment with a view to assessing the effect of the drug on disease.

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. Measurable disease according to RECIST 1.1 criteria. Patients participating in the
dose escalation part of Arm 2 only require assessable disease.

7. Life expectancy >3 months.

8. Blood tests within the following parameters:

1. Platelet count ≥100 x10⁹/L

2. Haemoglobin ≥9g/dL (blood transfusion to achieve this level is permitted)

3. Calculated creatinine clearance ≥50 mL/min using the modified Cockroft-Gault
equation

4. Neutrophil count ≥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. Patients with a history of adrenal insufficiency, maintained on stable replacement
dose corticosteroid (<10 mg/d prednisone or the equivalent) are eligible for
treatment with IMCgp100, unless there is a past history of adrenal crisis. Eligible
patients with a history of adrenal insufficiency receiving replacement dose
corticosteroid must receive prophylactic stress dose corticosteroid prior to dosing
during the first four doses of IMCgp100 treatment, regardless of weekly or daily
dosing regimen.

12. Able to give informed consent.

Exclusion Criteria:

Patients meeting any of the following criteria will be excluded from the study:

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 nonmelanomatous 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. Symptomatic on-going 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.

12. Patients with evidence of a raised intracranial pressure in Arm 2 of the study who
will have a CSF sample taken.

13. Patients receiving chronic corticosteroid treatment (longer than 8 weeks duration)
for management of pre-existing adverse events at any dose, or patients with a history
of chronic corticosteroid treatment longer than 8 weeks duration for adverse events
within 6 months.