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

IMCgp100 is a new biological therapy designed for the treatment of melanoma skin cancer. The drug is designed to target melanoma cells and stimulate immune cells to kill them. This trial is designed to establish the level of drug that can be given to a patient that is tolerable. It also designed to establish the best dosing schedule for the drug and to look for signals that the drug is working as intended.

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, participants will receive an extended course of treatment with a view to assessing the effect of the drug on disease.

Eligibility Criteria:
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. Participants 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 localized radiotherapy has been applied, treatment with IMCgp100 can be commenced after a two week period.
3. Human leukocyte antigen (HLA) A2 positive.
4. ≥ 18 years old.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
6. Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Participants 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. Hemoglobin ≥ 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 participants 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 participants must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile.
10. Male participants must be surgically sterile or willing to use a double barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last study drug infusion.
11. Participants 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 participants 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:

Participants 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. Participants with corrected QT interval (QTc) calculated by Bazetts or locally preferred formula which is greater than 500 ms.
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 human immunodeficiency virus (HIV) infection.
11. Has a history of adult seizures.
12. Participants with evidence of a raised intracranial pressure in Arm 2 of the study who will have a cerebrospinal fluid sample taken.
13. Participants receiving chronic corticosteroid treatment (longer than 8 weeks duration) for management of pre-existing adverse events at any dose, or participants with a history of chronic corticosteroid treatment longer than 8 weeks duration for adverse events within 6 months.