| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced BRAF V600 mutant melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced BRAF V600 mutant 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 | 16.1 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| 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) |
|
| 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 overall response rate (ORR) of combination therapy with dabrafenib and trametinib in patients with advanced BRAF V600 mutant melanoma who are documented with progression of disease at least 12 weeks following the last dosing of a BRAF inhibitor containing treatment regimen. |
|
| E.2.2 | Secondary objectives of the trial |
•To estimate survival (PFS and OS) on dabrafenib for subjects with advanced/metastatic BRAF V600E/K mutation-positive melanoma.
•To characterize the safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma (SCC) and other proliferative cutaneous lesions |
|
| 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 cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive.
4. Subjects must have failed at least two prior systemic anti-cancer treatments for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma that must have included:
a. Treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, and LGX818) and progression of disease per RECIST, version 1.1 must have been documented during this treatment.
b. Treatment with ipilimumab (or an alternative experimental immunotherapy) and progression of disease per immune related response criteria must have been documented during this treatment.
5. Documented progression of disease per RECIST, version 1.1 or per immune related response criteria if the latest systemic therapy administered was ipilimumab, an anti-PD1 or anti-PD-L1 therapy, or any other experimental immunotherapy.
6. The presence of at least one measurable lesion per RECIST, version 1.1
7. 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 last administration of a BRAF-inhibitor;
b. > 12 weeks following the date of the first administration and > 4 weeks following the date of the last administration of ipilimumab, or an anti-PD1, or anti-PD-L1 therapy;
c. > 4 weeks following the date of the last administration of chemotherapy (> 6 weeks in case of a nitrosurea or mitomycin C containing regimen);
d. > 4 weeks following major surgery or extensive radiotherapy.
8. Subjects with ocular melanoma are not eligible.
9. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 2) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 at the time of recruitment.
10. 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.
11. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to recruitment and agree to use effective contraception, as defined in Section 7.3.3.1, throughout the treatment period, and for 4 months after the last dose of study treatment.
12. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
13. Adequate baseline organ function |
|
| E.4 | Principal exclusion criteria |
1. Grade 4 or repetitive grade 3 adverse event(s) related to prior treatment with a BRAF- and/or MEK inhibitor.
2. Prior treatment with a combination of a BRAF inhibitor and a MEK inhibitor (including but not limited to the combination of dabrafenib and trametinib or vemurafenib and cobimetinib, or LGX818 and MEK162)
3. Any contra-indication for evaluation by whole body CT and MRI of the brain.
4. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
5. Current use of a prohibited medication as described in Section 6 or requires any of these medications during treatment.
6. History of another malignancy, including any malignancy with confirmed activating RAS mutation. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility. 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) not including malignancy with confirmed activating RAS mutation, or subjects with a history of completely resected non-melanoma skin cancer.
7. 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.
8. 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).
9. Patients with progressive symptoms from active brain metastasis or in need of an increase in corticosteroids dose to control symptoms within 4 weeks prior to recruitment are excluded
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 ≥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), coronary angioplasty or stenting;
e. A history or evidence of current ≥Class II congestive heart failure
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;
h. 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. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
14. Females who are pregnant or nursing.
15. Interstitial lung disease or pneumonitis |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Overall 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessment of tumor response per RECIST, version 1.1 will be based on whole body CT- and/or MR-images every 8 weeks during study treatment. Tumor responses (CR or PR) will be confirmed by CT- and/or MR-imaging 4 weeks after the first documentation of response. |
|
| E.5.2 | Secondary end point(s) |
• Progression-free survival (PFS; defined as the time from randomization until the earliest date of disease progression or death due to any cause) and overall survival (OS; defined as the time from randomization until the date of death due to any cause).
• Safety as measured by clinical assessments including vital signs and physical examinations, 12-lead electrocardiograms (ECG), echocardiogram (ECHO), chemistry and hematology laboratory values, incidence of squamous cell carcinoma and adverse events (AEs). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS: week 8 and every 8 weeks thereafter (all +/- 7 days) until determination of progressive disease
- OS: Follow-up information (by clinical visit or by telephone inquiry) of surviving study patients will be collected at least every 6 months for up to 1 year from the date of last dose of study treatment in the last patient on study or until the death or lost to follow-up of the last patient on study (whatever event is observed first).
- Safety: throughout the study assessment of safety will be based on repeated clinical examination, blood analysis, and additional investigations as indicated. |
|
| 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
| 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 | 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
|
| Follow-up information (by clinical visit or by telephone inquiry) of surviving study patients will be collected at least every 6 months for up to 1 year from the date of last dose of study treatment in the last patient on study or until the death or lost to follow-up of the last patient on study (whatever event is observed first). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
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