E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anti-PD1-/ PD-L1-refractory/relapsed, unresectable Stage III or IV melanoma |
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E.1.1.1 | Medical condition in easily understood language |
Advanced black skin cancer that is resistant to approved therapies |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10072449 |
E.1.2 | Term | Desmoplastic melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024220 |
E.1.2 | Term | Lentigo maligna recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024218 |
E.1.2 | Term | Lentigo maligna |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024223 |
E.1.2 | Term | Lentigo maligna stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024224 |
E.1.2 | Term | Lentigo maligna stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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) |
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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 | 10025670 |
E.1.2 | Term | Malignant melanoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10025671 |
E.1.2 | Term | Malignant melanoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066600 |
E.1.2 | Term | Melanoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10027480 |
E.1.2 | Term | Metastatic malignant melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10079054 |
E.1.2 | Term | Naevoid melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10029488 |
E.1.2 | Term | Nodular melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10042551 |
E.1.2 | Term | Superficial spreading melanoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10042552 |
E.1.2 | Term | Superficial spreading melanoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10042553 |
E.1.2 | Term | Superficial spreading melanoma stage unspecified |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10027156 |
E.1.2 | Term | Skin melanomas (excl ocular) |
E.1.2 | System Organ Class | 100000004858 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the anti-tumor activity of BNT111 + cemiplimab (Arm 1) in terms of objective response rate (ORR) according to RECIST 1.1 |
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E.2.2 | Secondary objectives of the trial |
•To assess the anti-tumor activity of each single-agent (i.e., BNT111 and cemiplimab, respectively) in terms of ORR according to RECIST 1.1. •To assess additional measures of antitumor activity of BNT111 + cemiplimab (Arm 1), and each single agent according to RECIST 1.1. •To assess overall survival of BNT111 + cemiplimab (Arm 1). •To assess the safety and tolerability profile of BNT111 + cemiplimab (Arm 1), and each single agent (i.e., monotherapy of BNT111 and cemipilmab). •To assess health-related quality of life (HRQoL) of patients treated with BNT111 + cemiplimab (Arm 1) and of patients receiving BNT111 and cemiplimab as single agents as measured by the European organization for research and treatment of cancer quality-of-Life questionnaire core 30 items (EORTC QLQ-C30). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients must have histologically confirmed unresectable Stage III or IV (metastatic) cutaneous melanoma and measurable disease by RECIST 1.1.
• Patients must have confirmed disease progression on/after approved anti-PD1/ PD-L1 regimen for melanoma as defined by RECIST 1.1
• Previous exposure to approved anti-PD1/ PD-L1 containing regimen for at least 12 consecutive weeks and
- Current radiological progression to be confirmed by 2 scans 4-12 weeks apart. If progression is accompanied by new symptoms or deterioration of performance status (PS) not attributed to toxicity, one scan is sufficient and
-Inclusion into this trial must be within 6 months of confirmation of disease progression on anti-PD-1/PD-L1 treatment, regardless of any intervening therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
• Patients must have serum lactate dehydrogenase (LDH) ≤ ULN.
Please refer to the protocol for a full description of the inclusion criteria.
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E.4 | Principal exclusion criteria |
• History of uveal, acral, or mucosal melanoma.
• Ongoing or recent evidence (within the last 5 years) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may suggest risk for immune-related adverse events (irAEs). Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related hypothyroidism who are in remission, or on a stable dose of thyroid-replacement hormone, vitiligo, or psoriasis may be included.
• Systemic immune suppression within 14 days prior to randomization: − Use of chronic systemic steroid medication (up to 5 mg/day prednisolone equivalent is allowed); patients using physiological replacement doses of prednisone for adrenal or pituitary insufficiency are eligible, − Other clinically relevant systemic immune suppression.
Please refer to the protocol for a full description of the exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• ORR defined as the proportion of patients in whom a complete response (CR) or partial response (PR) is observed as best overall response by blinded independent central review (BICR). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Blinded centralized review and response assessment according to RECIST 1.1/iRECIST will take place on a continuous basis. • Assessment of Health Related Quality of Life will be done on a continuous bases at pre-specified time points |
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E.5.2 | Secondary end point(s) |
• ORR defined as the proportion of patients in whom a CR or PR is observed as best overall response by BICR.
• Duration of response (DOR) defined as the time from first objective response (CR or PR) to first occurrence of objective tumor progression (progressive disease, PD) by BICR or death from any cause (whichever occurs first).
• Disease control rate (DCR) defined as the proportion of patients in whom a CR, PR or stable disease (SD; assessed at least 6 weeks [wks] +/- 1 wk after first dose) is observed as best overall response by BICR.
• Time to response (TTR) defined as the time from randomization to the first objective tumor response (CR or PR) by BICR.
• Progression-free survival (PFS) defined as the time from randomization to first objective tumor progression (PD) by BICR or death from any cause (whichever occurs first).
• ORR, DOR, DCR, TTR, PFS, as assessed by the investigator.
• Overall survival (OS) defined as the time from randomization to death from any cause
• Occurrence of treatment-emergent adverse events (TEAE) within a patient including Grade ≥3 serious and/or fatal TEAE by relationship.
• Occurrence of immune-related adverse events (irAE).
• Occurrence of dose reduction and discontinuation of trial treatment within a patient due to TEAE.
• Changes in laboratory parameters compared to baseline.
• Occurrence of abnormal laboratory parameters within a patient.
• Changes in vital signs parameters compared to baseline.
• Occurrence of abnormal vital signs parameters within a patient.
• Mean changes from baseline in the global health status score of the EORTC- QLQ-C30
• Mean changes from baseline in scores of the EORTC QLQC30 functional and symptoms scales
• Time to first clinically meaningful deterioration in global health status score as measured by EORTC QLQ-C30
• Time to first clinically meaningful deterioration in symptoms and functioning as measured by EORTC QLQ-C30 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Blinded centralized review and response assessment according to RECIST 1.1/iRECIST will take place on a continuous basis.
• DOR defined as the time from first objective response (CR/PR) to first occurrence of objective tumor progression (progressive disease, PD) by BICR or death from any cause.
• DCR defined as the proportion of patients in whom a CR, PR or stable disease (SD; assessed at least 6 weeks [wks] +/- 1 wk after first dose) is observed as best overall response by BICR.
• TTR defined as the time from randomization to the first objective tumor response (CR or PR) by BICR.
• PFS defined as the time from randomization to first objective tumor progression (PD) by BICR or death from any cause.
•OS defined as the time from randomization to death from any cause.
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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 | No |
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 | Yes |
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 | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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 |
United Kingdom |
United States |
Germany |
Italy |
Poland |
Spain |
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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
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The end of the trial will be declared at the time at which: • all patients have discontinued trial treatment; and • all patients have completed safety follow-up assessment at day 90 subsequent to last dose; and • all patients have been followed-up for at least 24 months subsequent to first dose or • the sponsor discontinues the trial. |
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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 | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |