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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 : November 9, 2021
Sponsor:
Information provided by (Responsible Party):
Immunocore Ltd

Tracking Information
First Submitted Date  ICMJE February 14, 2017
First Posted Date  ICMJE March 3, 2017
Results First Submitted Date  ICMJE August 17, 2021
Results First Posted Date  ICMJE September 14, 2021
Last Update Posted Date November 9, 2021
Actual Study Start Date  ICMJE October 16, 2017
Actual Primary Completion Date October 13, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 17, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 28, 2017)
Overall survival defined as the time from patient inclusion to date of death due to any cause [ Time Frame: Survival status will be assessed every 3 months from randomization until death, assessed up to 40 months. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2021)
  • 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.
  • 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.
  • 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 21 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.
  • 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 21 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.
  • 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 21 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.
  • Pharmacokinetics (PK): Tebentafusp Concentration [ Time Frame: 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. ]
    Serum PK concentrations of tebentafusp were collected over time.
  • 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).
  • 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.
  • 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)
  • 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. ]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2017)
  • Safety defined as the number of patients with treatment emergent adverse events, laboratory abnormalities, ECG changes, and/or physical examination findings [ Time Frame: Safety will be assessed from informed consent through 90 days after end of treatment ]
  • Efficacy: Objective response rate (ORR) defined as the proportion of patients achieving an objective response (RECIST v1.1) by Independent Central Review [ Time Frame: ORR will be assessed every 3 months from randomization until disease progression, assessed up to 40 months ]
  • Efficacy: Duration of response (DOR) defined as the time from first documented objective response (RECIST v1.1) by Independent Central Review until the date of documented disease progression [ Time Frame: DOR will be assessed every 3 months from randomization until disease progression, assessed up to 40 months ]
  • Efficacy: Progression free survival (PFS) defined as the time from randomization to the date of progression (RECIST v1.1) by Independent Central Review or death due to any cause [ Time Frame: PFS will be assessed every 3 months from randomization until disease progression or death, assessed up to 40 months ]
  • Efficacy: Disease control rate (DCR) defined as the proportion of patients with either an objective response or stable disease (RECIST v1.1) by Independent Central Review. [ Time Frame: DCR will be assessed every 3 months from randomization until disease progression, assessed up to 40 months ]
  • Quality-of-Life: General health status will be assessed using the EQ-5D,5L questionnaire [ Time Frame: : EQ-5D,5L will be assessed every 6 weeks from randomization for 24 weeks and approximately every 3 months thereafter until death, assessed up to 40 months ]
  • Quality-of-Life: Health related quality of life will be assessed using EORTC QLQ-C30 questionnaire [ Time Frame: EORTC QLQ-C30 will be assessed every 6 weeks from randomization for 24 weeks and approximately every 3 months thereafter until disease progression, assessed up to 40 months ]
  • Pharmacokinetics (IMCgp100 Arm only): Area under the plasma concentration-time curve (AUC) [ Time Frame: AUC will be assessed weekly for 3 weeks and every 6 weeks thereafter until end of treatment, assessed up to 40 months ]
  • Pharmacokinetics (IMCgp100 Arm only): The maximum observed plasma drug concentration after single dose administration (Cmax) [ Time Frame: Cmax will be assessed weekly for 3 weeks and every 6 weeks thereafter until end of treatment, assessed up to 40 months ]
  • Pharmacokinetics (IMCgp100 Arm only): The time to reach maximum plasma concentration (Tmax) [ Time Frame: Tmax will be assessed prior to and after the first three doses of IMCgp100, an average of 3 weeks ]
  • Pharmacokinetics (IMCgp100 Arm only): The elimination half-life (t1/2) [ Time Frame: t1/2 will be assessed prior to and after the first three doses of IMCgp100, an average of 3 weeks ]
  • Pharmacokinetics (IMCgp100 Arm only): To assess the 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 40 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma
Official Title  ICMJE 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
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Uveal Melanoma
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Experimental: IMCgp100
    Biologic:IMCgp100 (Soluble gp 100-specific T cell receptor with anti - CD3 scFV: IMCgp100)
    Intervention: Biological: IMCgp100
  • 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

    Interventions:
    • Drug: Dacarbazine
    • Biological: Ipilimumab
    • Biological: Pembrolizumab
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 23, 2020)
378
Original Estimated Enrollment  ICMJE
 (submitted: February 28, 2017)
327
Estimated Study Completion Date  ICMJE March 2023
Actual Primary Completion Date October 13, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   France,   Germany,   Italy,   Netherlands,   Poland,   Russian Federation,   Spain,   Switzerland,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03070392
Other Study ID Numbers  ICMJE IMCgp100-202
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Immunocore Ltd
Study Sponsor  ICMJE Immunocore Ltd
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mohammed Dar Immunocore Ltd
PRS Account Immunocore Ltd
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP