| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer which starts and spreads from the pigmented cells of the eye |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025650 |
| E.1.2 | Term | Malignant melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The dual primary objectives are:
1) to compare the OS in all patients randomized to the tebentafusp monotherapy versus all patients randomized to the Investigator’s Choice monotherapy
2) to compare the OS in all patients randomized to the tebentafusp monotherapy who develop a rash within the first week of treatment versus all patients randomized to the Investigator's Choice monotherapy
Both objectives relate to HLA A*0201 positive patients with advanced UM with no prior treatment in the metastatic setting. |
|
| E.2.2 | Secondary objectives of the trial |
• To characterize the safety and tolerability of IMCgp100 in the intra-patient dose escalation regimen
• To characterize the PK profile of single-agent IMCgp100 in the intra-patient dose escalation regimen
• To assess the anti-tumor efficacy of IMCgp100 versus Inv. choice with the parameters of ORR, progression free survival, duration of response, time to response and disease control rate using response evaluation criteria in solid tumors
• To evaluate the treatment and disease impact to health-related quality of life in patients treated with IMCgp100 versus patients treated with Investigator’s Choice. HRQoL will be assessed using 2 established patient-reported outcome instruments:
o EuroQol-5 compared to population norms
o The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core
• To evaluate the incidence of anti-IMCgp100 antibody formation following multiple infusions of IMCgp100 in the intra-patient dose escalation regimen |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study must meet all of the following 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 local, liver-directed therapy including chemotherapy, radiotherapy, radiofrequency ablation (RFA), or embolization
• Prior surgical resection of oligometastatic liver 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 Investigator’s Choice therapy that was administered as adjuvant or neoadjuvant treatment
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 must have measurable disease according to RECIST v.1.1
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 |
|
| E.4 | Principal exclusion criteria |
1.Patient with any out-of-range lab. values:
Serum creatinine > 1.5 × upper limit of normal (ULN) &/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min, Total bilirubin > 1.5 × ULN, exc. for patients with Gilbert's syndrome who are excluded if tot. bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN, Alanine aminotransferase > 3 × ULN, Aspartate aminotransferase > 3 × ULN, Absolute neutrophil count < 1.0 × 10^9/L, Absolute lymphocyte count < 1.0 × 10^9/L, Platelet count < 75 × 10^9/L, Hemoglobin < 8 g/dL, Potassium, magnesium, corrected calcium or phosphate abnormality of NCI CTCAE (v4.03) > grade 1
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 &/or uncontrolled heart disease such as congestive heart failure (NYHA grade = 2), uncontrolled hypertension, or clinically significant arrhythmia currently requiring medical treatment
•QT interval corrected by Fridericia`s formula (QTcF) > 470 msec on screening ECG or congenital long QT syndrome
•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 MRI prior to the first dose of study drug
5.Active infection requiring syst. antibiotic therapy. Patients requiring syst. antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug 6.Known history of HIV infection
7.Active HBV or HCV infection per institutional protocol
8.Malignant disease, other than that being treated in this study. Exception: 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.Medical condition that would, in the invest.'s or Sponsor's judgment, prevent the patient's participation 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. 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);16.Radiotherapy within 2 weeks of the first dose of study drug, exception: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, GMCSF, M-CSF) = 2 weeks prior to start of study drug. An erythroidstimulating 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
19.Women of childbearing potential who are sexually active with a nonsterilized male partner, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during study treatment, 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.
20.Male patients surgically sterile or using 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 related to the investigator or any subinv., 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 as per applicable labeling. Patient may have a contraindication to 1 or 2 of the choices if she/he is a candidate for dosing with at least one Inv.Choice and meets all other study eligibility criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is OS, date of death in relation to study enrollment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| throughout the whole trial |
|
| E.5.2 | Secondary end point(s) |
1) Tolerability: Dose interruptions, reductions, and dose intensity of all administered agents
2) Serum PK parameters (eg, area under the curve (AUC), Cmax, time of maximum concentration (Tmax), t1/2)
3) Tumor response over time as determined by RECIST v.1.1 response criteria based on blinded independent central review (BICR)
4) Additional measures of efficacy including ORR, PFS, DOR, time to response and DCR (defined at 24 weeks)
5) EQ-5D,5L and EORTC QLQ C30 change from Baseline over time and between treatment strategies
6) Assessments of anti-IMCgp100 antibody formation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) throughout the whole trial
2) see protocol table 7-6
3) Screening, Every 12 weeks from C5D1 until confirmed PD per irRECIST or patient withdrawal. After EOT, during PD follow-up, every 12 weeks until PD per irRECIST or lost to follow-up
4) throughout the whole study
5) C1D1, on D1 of every other cycle to C5D1, every 4th cycle thereafter beginning with C9D1, and EOT. Disease Progression FU and survival FU: every 3M
6) Predose C1D1, C1D8, C2D1, C3D1, C5D1, C7D1, C9D1, C11D1, C13D1, EOT at visit
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Russian Federation |
| Ukraine |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study will be the last visit of the last patient undergoing the study. All patients will have completed follow-up for OS by the final DCO, which will occur when approximately 219 deaths have occurred. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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