E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
unresectable stage III/IV melanoma |
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E.1.1.1 | Medical condition in easily understood language |
skin cancer that has spread out through the body |
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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 | 14.1 |
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 | 100000004864 |
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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 |
Primary objectives: To assess the ability of dabrafenib + trametinib treatment to downsize melanoma tumor masses to enable R0-resection.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: Recurrence free survival; time-to-next treatment, overall survival. |
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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 |
Objectives translational research: To investigate treatment induced changes in exome mutations within the tumor, changes in gene expression profiles and development of gene signatures for response to treatment, target protein inhibition (levels of pMEK, pERK, pAKT) and IHC for lymphocytic infiltrates and expression of PD-L1, Gata-3, IDO etc.) To perform patient derived xenografting (PDX) in immunodeficient mice to investigate development of resistance.
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E.3 | Principal inclusion criteria |
1. Patients have provided signed informed consent. 2. Patients have unresectabel stage III melanoma (documented and based on MSD) or stage IV melanoma with ≤ 3 resectable metastases/organ site. 3. Patients have pathologically confirmed BRAF mutation-positive (V600E/K) melanoma as determined via in-house testing with a BRAF mutation assay. 4. Patients are treatment naïve for unresectable melanoma. 5. Patients for whom the intended operation is considered to offer a chance of cure or substantial palliation. 6. Patients have evaluable disease by CT/MRI or PET with ≤ 3 metastases/organ sites. 7. Patients are ≥18 years of age. 8. Patients are able to swallow and retain oral medication. 9. Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study. 10. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment. 11. Patients have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 12. Patients must have adequate organ function as defined in the protocol. Treatment with transfusion, growth factors to meet eligibility criteria will not be allowed.
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E.4 | Principal exclusion criteria |
1. Patients with known ocular or primary mucosal melanoma. 2. Patients who used any investigational anti-cancer or other drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of dabrafenib + trametinib. 3. Patients who currently use a prohibited medication or are expected to require any of these medications during treatment with dabrafenib and trametinib. 4. Patients who had any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. 5. Patients with active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. 6. Patients with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency. 7. Patients with a history of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible 8. Patients with a history of alcohol or drug abuse within 6 months prior to screening. 9. Patients with psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, or unwillingness or inability to follow the procedures required in the protocol. 10. Patients with the cardiac abnormalities as defined in the protocol. 11. Pregnant or lactating female. 12. Patients with CNS metastases.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is the % of patients in whom an R0-resection could be performed. This is measured by the pathologist, who handles the resection material (no positive margins) and negative CT-scans. Patients that develop a CR on systemic treatment will of course be included in the analysis. The aim of the study is to enable R0 resection. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
8 weeks after start study treatment. |
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E.5.2 | Secondary end point(s) |
As the secondary endpoint recurrence-free survival will be assessed every 3 months by physical exam and CT-scan for 2 years, thereafter every 6 months for 2 year, and once in year 5. Thereafter by physical exam only. This will be assessed only in patients that undergo radical surgery. For patients not undergoing surgery, PFS will be assessed. Time to next treatment is defined as the moment the study treatment starts until start of any following treatment (surgery, RT or systemic treatment) for new lesions. This will be measured in all patients, but patients will be stratified for undergoing surgery or not undergoing surgery. Overall survival will be measured using Kaplan-Meier estimation for the total group of patients as well, again stratified for patients undergoing surgery or no surgery. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During follow-up of the patient. |
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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 | No |
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 | No |
E.8.1.1 | Randomised | No |
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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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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It is a two-stage design. If the response in the first 14 patients is sufficient, than another 11 will be treated. The end of trial could be LVLS of the first stage (14 patients), or LVLS of the second stage (25 patients). |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |