| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic melanoma with BRAF mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced skin cancer with a genetic abnormality |
|
| 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 | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 define the drug combination and sequencing strategy which leads to the best overall survival in patients with advanced melanoma and BRAF mutations. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of the two sequencing combination treatments on:
- Total progression-free survival (PFS), i.e. how long participants survive without the disease progressing
- The 3-year PFS rate, i.e. how many participants survive 3 years without disease progression
- Percentage of patients alive at 2 and 3 years
- Best overall response rate (BORR), i.e. the best response or remission achieved
- Duration of response (DoR), i.e. how long the response or remission lasts
- Biological markers: the biomarkers ancillary study will be conducted in a subgroup of participants to investigate the mechanisms of drug action and resistance, and how best to sequence the target and immunotherapy agents
- Toxicity of the investigational medicinal products (IMPs)
- Quality of life and general health status defined by:
- Health-related quality of life (HRQoL), by means of the 30-item European
Organisation for Research and Treatment of Care quality of life questionnaire
(EORTC QLQC30) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biomarker (Biological) Ancilliary Study
The ancilliary study involves obtaining tumour biopsy samples and peripheral blood samples at particular timepoints in the study - at baseline visits, week 4 and at disease progression. The objective is to understand both the mechanisms of drug action and development of drug resistance. In particular, the ancilliary study will inform the sequencing of target agents with immunotherapy agents. |
|
| E.3 | Principal inclusion criteria |
A subject is eligible for the study if all of the following criteria are met:
1) Patients of either sex aged ≥ 18 years
2) Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma) are eligible for study participation
3) Patients who are treatment naive for metastatic disease. Previous adjuvant treatment, including checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 are allowed except for stage IV (if completed at least 6 weeks prior to randomisation, and all related adverse events have either returned to baseline or stabilised). BRAF inhibitor treatment in an adjuvant setting is not permitted.
4) Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) as per RECIST 1.1 criteria
5) Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment
6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
7) Tumour tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. An archive sample is mandatory at the screening visit; however, a fresh sample would be preferable
8) Female subjects of childbearing potential must have a negative pregnancy test result at baseline and must practice two highly effective methods of contraception for the total study duration plus 23 weeks (i.e. 30 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab. Additional pregnancy tests must be performed every six weeks during the Combo-Immuno and every four weeks during the Combo-Target, as well as at the end of the systemic exposure
9) Men who are sexually active with women of childbearing potential must practice a reliable method of contraception for the total study duration plus 31 weeks (i.e. 80 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab
10) Adequate bone marrow haematological function: absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L AND platelet count ≥ 100 x 10*9/L AND haemoglobin ≥ 9 g/dL
11) Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 X ULN (< 5 x ULN if liver metastases)
12) Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥ 50 mL/min in females (calculated according to Cockroft-Gault formula)
13) Serum calcium levels, international normalised ratio (INR) and partial thromboplastin time within normal limits
14) Life expectancy of at least 3 months
15) Ability to understand study-related patient information and provision of written informed consent for participation in the study
|
|
| E.4 | Principal exclusion criteria |
A subject is excluded from the study if any of the following criteria are met:
1) Active brain metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
2) Subjects with active, known or suspected autoimmune disease
3) Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment
4) Prior treatment for stage III (unresectable) or stage IV melanoma with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody
5) Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who are of childbearing potential and not practicing a reliable method of birth control
6) Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study
7) Patients with a history of uncontrolled cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy (past or present evidence of retinopathy, central serous retinopathy [CSR], occlusion of retinal vein [RVO], retinal degenerative disease) or ophthalmopathy, which according to the ophthalmologic evaluation at baseline could be considered a risk factor for CSR / RVO (e.g. cupping of the optic disc, visual field defect, intraocular pressure (e.g. central intraocular pressure > 21 mmHg)
8) Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumour treated curatively and without evidence of recurrence for at least 3 years prior to study entry
9)History of Gilbert's syndrome
10) Inability to regularly access centre facilities for logistical or other reasons
11) History of poor co-operation, non-compliance with medical treatment, or unreliability
12) Participation in any interventional drug or medical device study within 30 days prior to treatment start
13) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
14) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival, calculated as the time from the date of randomization until the date of death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Date of death will be recorded for participants who die during the study; patients not known to have died at the end of the trial will be censored at the time of the last recorded date on which the patient was known to be alive. |
|
| E.5.2 | Secondary end point(s) |
- Total PFS
- Three-year PFS rate
- Percentage of patients alive at 2 and 3 years
- Best overall response rate (BORR)
- Duration of response (DoR)
- Biological markers (biomarkers) ancilliary study (hypothesis-generating only)
- Quality of life and general health status
Safety endpoints
- Toxicity profile of the IMPs
- Adverse event and serious adverse event profile
- Vital sign safety profile
- Laboratory parameter safety profile
Biomarker ancilliary (sub-study) endpoints:
Tumour tissie biomarkers
- Immune status: CD3, CD8 and CD4-T cells; Activated T cells; Regulatory T cells; Dendritic cells
- Development of resistance to immunotherapy agents: Checkpoint receptors/ligands; Myeloid-derived suppressor cells
- Development of resistance to target therapy agents:Aberrations in MEK/PI3K pathways; Cytokines that interact with tyrosine kinase receptors
- Mutational load and neoantigen profile
Peripheral blood biomarkers:
- Immune status/resistance to immunotherapy agents: Activated T cells; Memory/Exhausted T cells; T regulatory cells; MDSCs; Inflammatory response; C-reactive protein; TCR Sequencing/Gene Expression analysis
• Response/resistance to targeted agents: Apoptotic tumor cells; soluble hepatocyte growth factor; serum vascular endothelial growth factor, soluble interleukin-2 receptor.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Total PFS: calculated from the date of randomisation to the date of second progression. Any progression or death will be considered an event if the participant cannot complete the treatment sequence
- Three-year PFS: calculated from the date of randomisation to the 3 year timepoint
- Percentage of patients alive at 2 and 3 years: calculated from the date of randomisation to the 2 and 3 year timepoints
- Best overall response rate (BORR): calculated from the date of randomisation to the date of progression
- Duration of response (DoR): calculated from the date of first documented response to the date of the first documented progression or death
- Quality of life and general health status: end of study status compared to baseline |
|
| 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 | No |
| 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 | No |
| E.8.1.2 | Open | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| 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 | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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