| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cutaneous melanoma - aggressive form of skin cancers. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable or metastatic BRAF-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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040808 |
| E.1.2 | Term | Skin cancer |
| 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 establish the superiority of dabrafenib and trametinib combination therapy over dabrafenib and trametinib placebo (dabrafenib monotherapy) with respect to progression-free survival (PFS) for subjects with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare dabrafenib and trametinib combination therapy with dabrafenib monotherapy for overall survival (OS), overall response rate (ORR), and duration of response
• To characterize the safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma (SCC) and other proliferative cutaneous lesions; and
• To characterize the concentrations of trametinib and of dabrafenib and its metabolites in subjects in the combination arm and of dabrafenib and its metabolites in the dabrafenib monotherapy arm. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following 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 (metastic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). The assay will be conducted by a central reference laboratory.
Subjects with ocular or mucosal melanoma are not eligible.
4. Measurable disease (i.e., present with at least one measurable lesion per RECIST, version 1.1. Refer to Section 7.2.3.1 of protocol for
the definition of a measureable lesion.
5. All prior anti-cancer treatment-related toxicities (except alopecia) and laboratory values must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 at the time of randomization.
6. 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.
7. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception, as defined in Section 7.3.3 of protocol, throughout the treatment period, and for 30 days after the last dose of
study treatment.
Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 7.3.3 of protocol from 14 days prior to randomization, throughout the treatment period, and for 16 weeks after the last dose of study treatment.
8. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Adequate baseline organ function as defined in Table 2 (page 25 of Protocol).
10. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119).
2. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.)
3. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization.
4. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization.
5. Current use of a prohibited medication as described in Section 6.2.
6. History of another malignancy.
Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer, and/or subjects with indolent second malignancies are eligible.
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 (with the exception of chronic or cleared HBV and HCV infection which will be allowed).
9. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
10. Brain metastasis are excluded unless:
a. All known lesions were previously treated with surgery or stereotactic
surgery (whole-brain radiation is not allowed unless given after definitive
treatment with surgery or stereotactic surgery), AND
b. Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for ≥ 12 weeks prior to randomization (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND
c. Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to randomization, AND
d. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomization In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for ≥12 weeks is required and must be confirmed by two consecutive scans, separated by ≥6 weeks, prior to randomization.
11. A history or evidence of cardiovascular risk including any of the following:
a. LVEF < LLN
b. A QT interval corrected for heart rate using the Bazett’s formula (QTcB; Appendix 3) ≥480 msec;
c. A history or evidence of current clinically significant uncontrolled
arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to randomization are eligible.
d. A history (within 6 months prior to randomization) of acute coronary
syndromes (including myocardial infarction or unstable angina), coronary
angioplasty;
e. A history or evidence of current ≥Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines (Appendix 4 of protocol);
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. A history or current evidence/risk of retinal vein occlusion (RVO) or 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.
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 nursing. |
|
| E.5 End points |
| E.5.1 | Primary 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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 8 and every 8 weeks thereafter through week 56 and then every 12 weeks thereafter (all +/- 7 days) until determination of progressive disease |
|
| E.5.2 | Secondary end point(s) |
Overall survival (OS; defined as the time from randomization until death due to any cause).
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.
Duration of response (defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response [i.e., confirmed or unconfirmed CR or PR]).
Safety as measured by clinical assessments including vital signs and physical examinations, 12-lead electrocardiograms (ECG), echocardiogram (ECHO), chemistry and hematology laboratory values, and adverse events (AEs).
Concentrations of trametinib and of dabrafenib and its metabolites (GSK2285403, GSK2298683, and GSK2167542) in the combination arm and dabrafenib and its metabolites in the dabrafenib monotherapy arm.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS will be assessed every 12 weeks after treatment discontinuation
ORR and duration of response will be calculated based on the disease assessment schedule of Week 8 and every 8 weeks thereafter through week 56, and then every 12 weeks thereafter (all +/- 7 days) until determination of progressive disease
All safety assessments will be performed at baseline and then every 4 weeks, except ECG and ECHOs, which will be done every 12 weeks.
PK samples will be collected every 8 weeks through week 24. Three blood samples will be collected at Week 8: predose, 1-3 hours post dose, and 4-6 hours post dose. One blood sample will be obtained at Weeks 16 and 24.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Argentina |
| Australia |
| Canada |
| Russian Federation |
| Ukraine |
| United States |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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