Clinical trial NCT03070392: Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Uveal Melanoma
Keywords: 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
Lead sponsor: Immunocore Ltd
Sponsor class: INDUSTRY
First posted: 2017-03-03
Enrollment: 378
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Primary outcomes:
measure: Efficacy: Overall Survival
timeFrame: From randomization to the data cut off date of 13-Oct-2020; median follow-up duration was 14.1 months.
Secondary outcomes:
measure: Safety: Number of Participants With Treatment Emergent Adverse Events
timeFrame: Safety was assessed from informed consent through 90 days after end of treatment, up to 36 months.
measure: Efficacy: Progression Free Survival (PFS)
timeFrame: PFS was assessed every 3 months from randomization until disease progression or death, up to 36 months.
measure: Quality-of-Life: Change From Baseline in EQ-5D,5L Domain Scores
timeFrame: 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.
measure: Quality-of-life: Change From Baseline in EQ-5D Visual Analogue Score (VAS)
timeFrame: 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.
measure: Quality-of-Life: Change From Baseline in EORTC QLQ-C30 Global Health Status
timeFrame: 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.
measure: Pharmacokinetics (PK): Tebentafusp Concentration
timeFrame: 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.
measure: Efficacy: Objective Response Rate (ORR)
timeFrame: ORR will be assessed after every participant has had at least 3 assessments, conducted every 3 months, up to 5.5 years.
measure: Efficacy: Duration of Response (DOR)
timeFrame: DOR will be assessed every 3 months from randomization until disease progression, assessed up to 5.5 years.
measure: Efficacy: Disease Control Rate (DCR)
timeFrame: DCR will be assessed every 3 months from randomization until disease progression, up to 5.5 years.
measure: Pharmacokinetics: Frequency of Anti-IMCgp100 Antibody Formation
timeFrame: Approximately 5 assessments will be performed between first dose of IMCgp100 and end of treatment, assessed up to 5.5 years.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute
state: California
city: Palo Alto
country: United States
facility: Byers Eye Institute, Stanford University
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Miami
country: United States
facility: University of Miami - Sylvester Comprehensive Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago Medicine
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Portland Providence Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: Houston Methodist Cancer Center
state: Texas
city: Darlinghurst
country: Australia
facility: Saint Vincents Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Central Adelaide Local Health Network, Royal Adelaide Hospital Cancer Center
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: Bruxelles
country: Belgium
facility: Institut Roi Albert II Cliniques Universitaires St-Luc
city: Bruxelles
country: Belgium
facility: Universite Catholique de Louvain Centre du Cancer, Medical Oncology
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
city: Nice
country: France
facility: Centre Atoine Lacassagne
city: Paris
country: France
facility: Institut Curie
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln Dermatologie und Venerologie
state: Nordrhein Westfalen
city: Berlin
country: Germany
facility: Charite - Campus Benjamin Franklin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Essen
country: Germany
facility: University Hospital Essen
city: Hamburg
country: Germany
facility: University of Hamburg
city: Heidelberg
country: Germany
facility: Nationales Centrum für Tumorerkrankungen
city: Munich
country: Germany
facility: Klinik und Poliklinik für Dermatologie und Allergologie
city: Milan
country: Italy
facility: Fondazione ICCRS
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori - IRCCS Fondazione "G. Pascale" - UOC Melanoma, Immunoterapia Oncologica e Terapie Innovative
city: Leiden
country: Netherlands
facility: LUMC Medical Oncology
city: Warsaw
country: Poland
facility: Centrum Onkologii - Instytut im. Marii Sklodowskiej-Curie
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Institution N.N. Blokhin National Medical Research Center of Oncology
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budget Institution National Medical Research Center of Oncology
city: L'Hospitalet De Llobregat
country: Spain
facility: Institut Catala d'Oncologia (ICO) - L'Hospitalet
state: ES-Spain
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
state: ES-Spain
city: Santiago De Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago de Compostela
state: ES-Spain
city: Valencia
country: Spain
facility: Hospital Universitario General de Valencia
state: ES-Spain
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Zürich
country: Switzerland
facility: University of Zurich Hospital
city: Dnipropetrovs'k
country: Ukraine
facility: Dnipropetrovsk State Medical Academy
city: Kyiv
country: Ukraine
facility: Kyiv Munitipal Hospital
city: Uzhhorod
country: Ukraine
facility: Uzhhorod Central City Clinical Hospital
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre
state: Middlesex
city: Bebington
country: United Kingdom
facility: The Clatterbridge Cancer Centre
state: Wirral
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
Study officials:
affiliation: Immunocore Ltd
name: Immunocore Medical Information
role: STUDY_DIRECTOR
References:
citation: 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.