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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Phase II Randomized, Open-label, Multi-center Study of the Safety and Efficacy of IMCgp100 Compared With Investigator Choice in HLA-A*0201 Positive Patients With Previously Untreated Advanced Uveal Melanoma

Conditions
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Uveal Melanoma

Intervention / Treatment
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* Biological: IMCgp100
* Drug: Dacarbazine
* Biological: Ipilimumab
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female patients age ≥ 18 years of age at the time of informed consent Ability to provide and understand written informed consent prior to any study procedures Histologically or cytologically confirmed metastatic UM 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. HLA A*0201 positive by central assay Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at Screening Patients have measurable disease or non-measurable disease according to RECIST v1.1 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 Out-of-range laboratory values History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies Clinically significant cardiac disease or impaired cardiac function, 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 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 Known history of human immunodeficiency virus infection (HIV). Testing for HIV status is not necessary unless clinically indicated 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 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 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 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 History of adrenal insufficiency History of interstitial lung disease History of pneumonitis that required corticosteroid treatment or current pneumonitis History of colitis or inflammatory bowel disease 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) 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 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 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) 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 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 Patients who are in an institution due to official or judicial order. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMCgp100 (tebentafusp, Kimmtrak)<br>Biologic:IMCgp100 (Soluble gp 100-specific T cell receptor with anti - CD3 scFV: IMCgp100) | Biological: IMCgp100<br>* IMCgp100 is to be administered at 20 mcg cycle 1 day1, then 30 mcg cycle 1 day 8, then 68 mcg cycle 1 day 15 and weekly thereafter by IV infusion over 15 minutes until confirmed disease progression or unacceptable toxicity<br>|
| Active Comparator: Investigator's Choice<br>1 of 3 Investigator's Choice options: Systemic Dacarbazine 1 of 3 Investigator's Choice options: Systemic Ipilimumab 1 of 3 Investigator's Choice options: Systemic Pembrolizumab | Drug: Dacarbazine<br>* Dacarbazine is to be administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity<br>* Other names: Imidazole Carboxamide;Biological: Ipilimumab<br>* Ipilimumab is to be administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments<br>* Other names: Yervoy;Biological: Pembrolizumab<br>* Pembrolizumab is to be administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Overall Survival | Overall survival is defined as the time from randomization to date of death due to any cause. | From randomization to the data cut off date of 13-Oct-2020; median follow-up duration was 14.1 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of Participants With Treatment Emergent Adverse Events | Safety was defined as the number of participants with treatment emergent adverse events, including laboratory abnormalities, ECG changes, and/or physical examination findings. | Safety was assessed from informed consent through 90 days after end of treatment, up to 36 months. | 
| Efficacy: Progression Free Survival (PFS) | Progression free survival (PFS) is defined as the time from randomization to the date of progression (RECIST v1.1) or death due to any cause. | PFS was assessed every 3 months from randomization until disease progression or death, up to 36 months. | 
| Quality-of-Life: Change From Baseline in EQ-5D,5L Domain Scores | General health status was assessed using the EQ-5D,5L questionnaire, which includes five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 scoring levels, where 1 indicates a better health state (no problems) and 3 indicates a worse health state. A positive change indicates improvement. | EQ-5D,5L was assessed at baseline (Cycle 1 Day 1) and on Day 1 of every other cycle to Cycle 5 Day 1, every fourth cycle thereafter, beginning with Cycle 9 Day 1 and End of Treatment (EOT), up to 36 months. Each cycle is 21 days. | 
| Quality-of-life: Change From Baseline in EQ-5D Visual Analogue Score (VAS) | The EQ-5D VAS score records the participant's self-rated health on a vertical visual analogue scale, with 0 being the worst imaginable health state and 100 being the best imaginable health state. A positive change indicates improvement. | EQ-5D,5L VAS was assessed at baseline (Cycle 1 Day 1) and on Day 1 of every other cycle to Cycle 5 Day 1, every fourth cycle thereafter, beginning with Cycle 9 Day 1 and End of Treatment (EOT), up to 36 months. Each cycle is 21 days. | 
| Quality-of-Life: Change From Baseline in EORTC QLQ-C30 Global Health Status | Global health status and quality of life was assessed using the EORTC QLQ-C30 questionnaire. The score range for the EORTC QLQ-C30 is from 0 to 100, with higher scores indicating better functioning and better global health status and health-related quality of life. A positive change indicates improvement. | EORTC QLQ-C30 was assessed at baseline (Cycle 1 Day 1) and on Day 1 of every other cycle to Cycle 5 Day 1, every fourth cycle thereafter, beginning with Cycle 9 Day 1 and End of Treatment (EOT), up to 36 months. Each cycle is 21 days. | 
| Pharmacokinetics (PK): Tebentafusp Concentration | Serum PK concentrations of tebentafusp were collected over time. | PK concentrations were assessed at pre-dose, end of infusion and anytime in the 12 to 24 hour window after completion of the infusion in Cycle 1 on Days 1, 8 and 15. | 
| Efficacy: Objective Response Rate (ORR) | Objective response rate (ORR) is defined as the proportion of patients achieving an objective response (RECIST v1.1). | ORR will be assessed after every participant has had at least 3 assessments, conducted every 3 months, up to 5.5 years. | 
| Efficacy: Duration of Response (DOR) | Duration of response (DOR) is defined as the time from first documented objective response (RECIST v1.1) until the date of documented disease progression. | DOR will be assessed every 3 months from randomization until disease progression, assessed up to 5.5 years. | 
| Efficacy: Disease Control Rate (DCR) | Disease control rate (DCR) is defined as the proportion of patients with either an objective response or stable disease (RECIST v1.1) | DCR will be assessed every 3 months from randomization until disease progression, up to 5.5 years. | 
| Pharmacokinetics: Frequency of Anti-IMCgp100 Antibody Formation |  | Approximately 5 assessments will be performed between first dose of IMCgp100 and end of treatment, assessed up to 5.5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Uveal Cancer, IMCgp100, Immunotherapy, Tebentafusp, Ocular Melanoma, Eye Melanoma, Uveal Melanoma, Gp100, TCR, Dacarbazine, Ipilimumab, Pembrolizumab, Bispecific T cell receptor fusion protein, ImmTAC, Immune mobilizing monoclonal T cell receptor against cancer, Kimmtrak