Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma

To evaluate the overall survival of HLA-A\*0201 positive adult patients with previously untreated advanced UM receiving IMCgp100 compared to Investigator's Choice of dacarbazine, ipilimumab, or pembrolizumab.

This Phase II study is designed to evaluate the safety and efficacy of IMCgp100 compared with Investigator's Choice (dacarbazine, ipilimumab or pembrolizumab) in HLA-A\*0201 positive adult patients with advanced UM treated in the first line setting with no prior systemic or liver-directed chemo-, radio- or immune-therapy administered in the advanced setting (prior surgical resection of liver metastases and adjuvant systemic therapy are acceptable). Comparison of the IMCgp100 efficacy results in this Phase II study will be made with the concurrently randomized arm (Investigator's Choice) with a primary endpoint of overall survival (OS) and secondary efficacy endpoints of progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and disease control rate (DCR).

Eligibility Criteria:
Inclusion Criteria

1. Male or female patients age ≥ 18 years of age at the time of informed consent
2. Ability to provide and understand written informed consent prior to any study procedures
3. Histologically or cytologically confirmed metastatic UM
4. Must meet the following criteria related to prior treatment:

   * No prior systemic therapy in the metastatic or advanced setting including chemotherapy, immunotherapy, or targeted therapy
   * No prior regional, liver-directed therapy including chemotherapy, radiotherapy, or embolization
   * Prior surgical resection of oligometastatic disease is allowed
   * Prior neoadjuvant or adjuvant therapy is allowed provided administered in the curative setting in patients with localized disease. Patients may not be re-treated with an Investigator's Choice therapy that was administered as adjuvant or neoadjuvant treatment. Additionally, patients who have received nivolumab as prior adjuvant/neoadjuvant treatment should not receive pembrolizumab as Investigator's Choice therapy.
5. HLA A\*0201 positive by central assay
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at Screening
7. Patients have measurable disease or non-measurable disease according to RECIST v1.1
8. All other relevant medical conditions must be well-managed and stable, in the opinion of the investigator, for at least 28 days prior to first administration of study drug

Exclusion Criteria

1. Out-of-range laboratory values
2. History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies
3. Clinically significant cardiac disease or impaired cardiac function,
4. Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require doses of corticosteroids within the prior 3 weeks to study Day 1. Patients with brain metastases are eligible if lesions have been treated with localized therapy and there is no evidence of PD for at least 4 weeks by magnetic resonance imaging (MRI) prior to the first dose of study drug
5. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug
6. Known history of human immunodeficiency virus infection (HIV). Testing for HIV status is not necessary unless clinically indicated
7. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection
8. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type
9. Any medical condition that would, in the investigator's or Sponsor's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
10. Patients receiving systemic steroid therapy or any other systemic immunosuppressive medication at any dose level, as these may interfere with the mechanism of action of study treatment. Local steroid therapies (eg, otic, ophthalmic, intra-articular, or inhaled medications) are acceptable
11. History of adrenal insufficiency
12. History of interstitial lung disease
13. History of pneumonitis that required corticosteroid treatment or current pneumonitis
14. History of colitis or inflammatory bowel disease
15. Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary)
16. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass
17. Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GM-CSF, M-CSF) ≤ 2 weeks prior to start of study drug. An erythroid-stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is not red blood cell transfusion dependent
18. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation)
19. Women of childbearing potential who are sexually active with a non-sterilized male partner, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during study treatment (defined in Section 6.7), and must agree to continue using such precautions for 6 months after the final dose of investigational product; cessation of birth control after this point should be discussed with a responsible physician. Highly effective methods of contraception are described in Section 6.7
20. Male patients must be surgically sterile or use double barrier contraception methods from enrollment through treatment and for 6 months following administration of the last dose of study drug
21. Patients who are in an institution due to official or judicial order.
22. Patients who are the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, or other staff thereof, directly involved in the conduct of the study.
23. Contraindication for treatment with Investigator's Choice alternatives (dacarbazine, ipilimumab and pembrolizumab) as per applicable labelling. Patient may have a contraindication to 1 or 2 of the choices if he/she is a candidate for dosing with at least 1 Investigator's Choice and meets all other study eligibility criteria.