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

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ClinicalTrials.gov Identifier: NCT03070392
Recruitment Status : Active, not recruiting
First Posted : March 3, 2017
Results First Posted : September 14, 2021
Last Update Posted : September 14, 2021
Sponsor:
Information provided by (Responsible Party):
Immunocore Ltd

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.

Condition or disease Intervention/treatment Phase
Uveal Melanoma Biological: IMCgp100 Drug: Dacarbazine Biological: Ipilimumab Biological: Pembrolizumab Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 378 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 16, 2017
Actual Primary Completion Date : October 13, 2020
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: IMCgp100
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:
  • DTIC-Dome
  • DTIC
  • DIC
  • 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 Name: 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 Name: Keytruda




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


Secondary Outcome Measures :
  1. Safety: Number of Participants With Treatment Emergent Adverse Events [ Time Frame: Safety was assessed from informed consent through 90 days after end of treatment, up to 36 months. ]
    Safety was defined as the number of participants with treatment emergent adverse events, including laboratory abnormalities, ECG changes, and/or physical examination findings.

  2. Efficacy: Progression Free Survival (PFS) [ Time Frame: PFS was assessed every 3 months from randomization until disease progression or death, up to 36 months. ]
    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.

  3. Quality-of-Life: Change From Baseline in EQ-5D,5L Domain Scores [ Time Frame: 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 28 days. ]
    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.

  4. Quality-of-life: Change From Baseline in EQ-5D Visual Analogue Score (VAS) [ Time Frame: 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 28 days. ]
    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.

  5. Quality-of-Life: Change From Baseline in EORTC QLQ-C30 Global Health Status [ Time Frame: 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 28 days. ]
    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.

  6. Pharmacokinetics (PK): Tebentafusp Concentration [ Time Frame: PK concentrations were assessed at pre-dose, end of infusion and 12-24 hours in Cycle 1 on Days 1, 8 and 15. ]
    Serum PK concentrations of tebentafusp were collected over time.

  7. Efficacy: Objective Response Rate (ORR) [ Time Frame: ORR will be assessed after every participant has had at least 3 assessments, conducted every 3 months, up to 5.5 years. ]
    Objective response rate (ORR) is defined as the proportion of patients achieving an objective response (RECIST v1.1).

  8. Efficacy: Duration of Response (DOR) [ Time Frame: DOR will be assessed every 3 months from randomization until disease progression, assessed up to 5.5 years. ]
    Duration of response (DOR) is defined as the time from first documented objective response (RECIST v1.1) until the date of documented disease progression.

  9. Efficacy: Disease Control Rate (DCR) [ Time Frame: DCR will be assessed every 3 months from randomization until disease progression, up to 5.5 years. ]
    Disease control rate (DCR) is defined as the proportion of patients with either an objective response or stable disease (RECIST v1.1)

  10. Pharmacokinetics: Frequency of Anti-IMCgp100 Antibody Formation [ Time Frame: Approximately 5 assessments will be performed between first dose of IMCgp100 and end of treatment, assessed up to 5.5 years. ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Life expectancy of > 3 months as estimated by the investigator
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at Screening
  8. Patients have measurable disease or non-measurable disease according to RECIST v1.1
  9. 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. Patient with any out-of-range laboratory values defined as:

    • Serum creatinine > 1.5 × upper limit of normal (ULN) and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/minute
    • Total bilirubin > 1.5 × ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN
    • Alanine aminotransferase > 3 × ULN
    • Aspartate aminotransferase > 3 × ULN
    • Absolute neutrophil count < 1.0 × 109/L
    • Absolute lymphocyte count < 0.5 × 109/L
    • Platelet count < 75 × 109/L
    • Hemoglobin < 8 g/dL
  2. History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies
  3. Clinically significant cardiac disease or impaired cardiac function, including any of the following:

    • Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association grade ≥ 2), uncontrolled hypertension or clinically significant arrhythmia currently requiring medical treatment
    • QT interval corrected by Fridericia's formula (QTcF) > 470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome. NOTE: If the initial automated QTcF is > 470 msec at screening, for the purpose of determining eligibility, the mean QTcF, based on at least 3 ECGs obtained over a brief time interval (ie, within 30 minutes), should be manually determined by a medically qualified person.
    • Acute myocardial infarction or unstable angina pectoris < 6 months prior to Screening
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03070392


Locations
Show Show 56 study locations
Sponsors and Collaborators
Immunocore Ltd
Investigators
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Study Director: Mohammed Dar Immunocore Ltd
  Study Documents (Full-Text)

Documents provided by Immunocore Ltd:
Study Protocol  [PDF] March 31, 2020
Statistical Analysis Plan  [PDF] October 28, 2020

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Responsible Party: Immunocore Ltd
ClinicalTrials.gov Identifier: NCT03070392    
Other Study ID Numbers: IMCgp100-202
First Posted: March 3, 2017    Key Record Dates
Results First Posted: September 14, 2021
Last Update Posted: September 14, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Immunocore Ltd:
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
Additional relevant MeSH terms:
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Melanoma
Uveal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Eye Neoplasms
Neoplasms by Site
Eye Diseases
Uveal Diseases
Pembrolizumab
Ipilimumab
Dacarbazine
Imidazole
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors