| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ADVANCED PRETREATED BRAFV600 WILD-TYPE MELANOMA |
|
| E.1.1.1 | Medical condition in easily understood language |
| ADVANCED PRETREATED BRAFV600 WILD-TYPE MELANOMA |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027150 |
| E.1.2 | Term | Melanoma malignant |
| 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 estimate the objective response rate of trametinib in patients with advanced pretreated BRAF wild-type melanoma (stratified by BRAF wild-type/NRAS mutant and BRAF/NRAS wild-type melanoma) |
|
| E.2.2 | Secondary objectives of the trial |
To estimate the progression-free (PFS) and overall survival (OS) of patients with advanced pretreated BRAF wild-type melanoma (stratified by BRAF wild-type/NRAS mutant and BRAF/NRAS wild-type melanoma)
To characterize the incidence and severity of adverse events of trametinib in patients with advanced pretreated BRAF wild-type melanoma (stratified by BRAF wild-type/NRAS mutant and BRAF/NRAS wild-type melanoma), with special interest in the possibility to manage trametinib-related treatment limiting skin toxicity by adding dabrafenib to the study treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age.
2. Signed written informed consent.
3. Histologically confirmed advanced melanoma that is either stage III (unresectable) or stage IV (metastatic)
4. Absence of a BRAF V600 mutation as determined by a validated test
5. In case of mucosal or acral melanoma, absence of a cKIT mutation as determined by a validated test
6. Presence of archival melanoma tissue of possibility of new biopsy.
7. Subjects must have failed at least prior systemic treatment with immune checkpoint inhibitors: CTLA-4 blocking immune checkpoint inhibitors (ipilimumab or other experimental anti-CTLA-4 antibodies), PD-1 blocking immune checkpoint inhibitors (pembrolizumab, nivolumab or other experimental anti-PD-1 antibodies), PD-L1 blocking immune checkpoint inhibitors. Progression of disease per RECIST, version 1.1 (Eisenhauer et al. Eur J Cancer 2009) or per immune related response criteria (Wolchok et al, Clin Cancer Res 2009) must have been documented during this treatment. Patients who are not able to undergo such treatment are also eligible.
8. The presence of at least one measurable lesion per RECIST, version 1.1 (Eisenhauer et al. Eur J Cancer 2009)
9. Interval between the date of the last administration of prior therapy for melanoma and the date of recruitment:
a. ≥ 12 weeks following the date of the first administration and ≥ 4 weeks following the date of the last administration of an anti-CTLA-4-, PD-1- or PD-L1 blocking immune checkpoint inhibitor;
b. ≥ 4 weeks following the date of the last administration of chemotherapy (≥ 6 weeks in case of a nitrosurea or mitomycin C containing regimen);
c. ≥ 4 weeks following major surgery or extensive radiotherapy.
10. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 1) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute (NCI) 2009) at the time of recruitment.
11. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
12. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to recruitment and agree to use effective contraception throughout the treatment period, and for 16 weeks after the last dose of study treatment.
13. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 14 days prior to administration of the first dose of study treatment, throughout the
treatment period, and for 16 weeks after the last dose of study treatment.
14. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Oken et al, Am J Clin Oncol 1982).
15. Adequate baseline organ function as defined in Table 1.
System
Laboratory values
Hematologic
Absolute neutrophil count
≥ 1.2 x 103/mm3
Hemoglobin
≥ 9.0 g/dL
Platelet count
≥ 75 x 103/mm3
PT/INR and APTTa
≤ 1.5 x ULN
Hepatic
Albumin
≥ 2.5 g/dL
Total bilirubin
≤ 1.5 x ULN
AST and ALT
≤ 2.5 x ULN
Renal
Calculated creatinine clearanceb
≥ 50 mL/min
Cardiac
Left ventriculair ejection fraction
≥ LLN by transthoracic echocardiogram
Abbreviations: APTT: activated partial thromboplastin time; ALT: alanine aminotransferase; AST: aspartate aminotransferase; INR: international normalized ratio; LLN: lower limit of normal; PT: prothrombin time; ULN: upper limit of normal.
a. Increase is allowed in the context of anticoagulant use.
b. By use of the Cockroft-Gault formula. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with uveal melanoma.
2. Prior treatment with MAPK-pathway inhibitors (BRAF inhibitors, MEK inhibitors)
3. Subjects with clinically active brain metastases (lesions should be stable and have been definitely treated with stereotactic radiation therapy, surgery or gamma knife therapy with no evidence of disease progression prior to enrollment.
4. Any contra-indication for evaluation by whole body FDG-PET/CT and MRI of the brain.
5. History of another malignancy. Exception: subjects who have been disease-free for 3 years, (i.e. subjects with second malignancies that are indolent or definitively treated at least 3 years ago) or subjects with a history of completely resected non-melanoma skin cancer.
6. Current use of any prohibited medication.
7. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
9. Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
10. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment
11. A history or evidence of cardiovascular risk including any of the following:
a. Current LVEF < LLN
b. A QT interval corrected for heart rate using the Bazett’s formula (QTcB) ≥ 480 msec;
c. A history or evidence of current clinically significant uncontrolled arrhythmias; exception: subjects with atrial fibrillation controlled for > 30 days prior to recruitment are eligible.
d. A history (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), or coronary angioplasty;
e. A history or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines;
f. Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy;
g. Patients with intra-cardiac defibrillators or permanent pacemakers;
h. Known cardiac metastases;
i. Abnormal cardiac valve morphology (≥ grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
12. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the QT interval.
13. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:
a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
b. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as:
i. Evidence of new optic disc cupping;
ii. Evidence of new visual field defects on automated perimetry;
iii. Intraocular pressure >21 mmHg as measured by tonography.
14. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
15. Females who are nursing. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, [Eisenhauer et al. Eur J Cancer 2009]) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS; defined as the time from recruitment until the earliest date of disease progression [per RECTIST v1.1] or death due to any cause) and overall survival (OS; defined as the time from recruitment until the date of death due to any cause)
Safety as measured by clinical assessments, including vital signs and physical examination, chemistry and hematology laboratory values, electrocardiograms, echocardiography, ophthalmologic examination and graded by the Common Terminology Criteria of Adverse events (CTCAE), |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 8 weeks and continue during the study |
|
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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
|
|
| 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 | 1 |
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