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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Uveal Melanoma
• Intervention / Treatment: Biological: IMCgp100; Drug: Dacarbazine; Biological: Ipilimumab; Biological: Pembrolizumab

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 378
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Saint Vincents Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Central Adelaide Local Health Network, Royal Adelaide Hospital Cancer Center
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Center
• Belgium
  • Bruxelles, Belgium
    • Institut Roi Albert II Cliniques Universitaires St-Luc
• Canada
  • Toronto, Canada, M5G 2M9
    • Princess Margaret Cancer Centre
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
• France
  • Nice, France, 6189
    • Centre Atoine Lacassagne
  • Paris, France, 75005
    • Institut Curie
• Germany
  • Berlin, Germany, 12200/12203
    • Charite - Campus Benjamin Franklin
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus
  • Essen, Germany
    • University Hospital Essen
  • Hamburg, Germany, 20246
    • University of Hamburg
  • Heidelberg, Germany, 69120
    • Nationales Centrum für Tumorerkrankungen
  • Munich, Germany, 80337
    • Klinik und Poliklinik für Dermatologie und Allergologie
  • Nordrhein Westfalen
    • Koeln, Nordrhein Westfalen, Germany, 50937
      • Universitaetsklinikum Koeln Dermatologie und Venerologie
• Italy
  • Milan, Italy, 20133
    • Fondazione ICCRS
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori - IRCCS Fondazione "G. Pascale" - UOC Melanoma, Immunoterapia Oncologica e Terapie Innovative
• Netherlands
  • Leiden, Netherlands, 2333
    • LUMC Medical Oncology
• Poland
  • Warsaw, Poland, 02-781
    • Centrum Onkologii - Instytut im. Marii Sklodowskiej-Curie
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Federal State Budgetary Institution N.N. Blokhin National Medical Research Center of Oncology
  • Saint Petersburg, Russian Federation, 197758
    • Federal State Budget Institution National Medical Research Center of Oncology
• Spain
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • ES-Spain
    • L'Hospitalet De Llobregat, ES-Spain, Spain, 08908
      • Institut Catala d'Oncologia (ICO) - L'Hospitalet
    • Madrid, ES-Spain, Spain, 28046
      • Hospital Universitario La Paz
    • Santiago De Compostela, ES-Spain, Spain, 15706
      • Hospital Clinico Universitario de Santiago de Compostela
    • Valencia, ES-Spain, Spain, 46014
      • Hospital Universitario General de Valencia
• Switzerland
  • Zürich, Switzerland, 8091
    • University of Zurich Hospital
• Ukraine
  • Dnipropetrovs'k, Ukraine, 49102
    • Dnipropetrovsk State Medical Academy
  • Kyiv, Ukraine, 02094
    • Kyiv Munitipal Hospital
  • Uzhhorod, Ukraine, 8800
    • Uzhhorod Central City Clinical Hospital
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Centre
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • Mount Vernon Cancer Centre
  • Wirral
    • Bebington, Wirral, United Kingdom, CH63 4JY
      • The Clatterbridge Cancer Centre
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute
    • Los Angeles, California, United States, 90024
      • UCLA Medical Center
    • Palo Alto, California, United States, 94303
      • Byers Eye Institute, Stanford University
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medicine
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma
  • Oregon
    • Portland, Oregon, United States, 97213
      • Portland Providence Medial Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IMCgp100 (tebentafusp, Kimmtrak); Biologic:IMCgp100 (Soluble gp 100-specific T cell receptor with anti - CD3 scFV: IMCgp100)	Biological: IMCgp100; 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
Active Comparator: Investigator's Choice; 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; 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; Other Names: DIC; DTIC; DTIC-Dome; Imidazole Carboxamide; Biological: Ipilimumab; Ipilimumab is to be administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Other Names: Yervoy; Biological: Pembrolizumab; 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; Other Names: Keytruda

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Immunocore Ltd
• Investigators: Study Director: Immunocore Medical Information, Immunocore Ltd

Publications and helpful links

General Publications

• Nathan P, Hassel JC, Rutkowski P, Baurain JF, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R, Kirkwood JM, Joshua AM, Sacco JJ, Shoushtari AN, Orloff M, Piulats JM, Milhem M, Salama AKS, Curti B, Demidov L, Gastaud L, Mauch C, Yushak M, Carvajal RD, Hamid O, Abdullah SE, Holland C, Goodall H, Piperno-Neumann S; IMCgp100-202 Investigators. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2021 Sep 23;385(13):1196-1206. doi: 10.1056/NEJMoa2103485.

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2017
• Primary Completion (Actual): October 13, 2020
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: February 14, 2017
• First Submitted That Met QC Criteria: February 28, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Pembrolizumab; Melanoma; Ipilimumab; TCR; ImmTAC; Bispecific T cell receptor fusion protein; Immune mobilizing monoclonal T cell receptor against cancer; Dacarbazine; Uveal Melanoma; Uveal Cancer; IMCgp100; Tebentafusp; Ocular Melanoma; Eye Melanoma; Gp100; Kimmtrak
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Eye Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Uveal Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Skin Neoplasms; Melanoma; Uveal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab; Dacarbazine; Ipilimumab; Imidazole
• Other Study ID Numbers: IMCgp100-202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No