| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with BRAF Mutation-Positive Melanoma that has Metastasized to the Brain |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic 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 assess the intracranial response (IR) of subjects with centrally confirmed BRAF V600E-mutation positive melanoma that has metastasized to the brain without symptoms and have not undergone prior local therapy for brain metastases (Cohort A). |
|
| E.2.2 | Secondary objectives of the trial |
• To assess cohort B for IR of subjects with locally confirmed BRAF V600E cutaneous melanoma with metastases to the brain confirmed by MRI, asymptomatic with prior local therapy for brain metastases;
• To assess cohort C for IR of subjects with locally confirmed BRAF V600 D/K/R cutaneous melanoma with metastases to the brain confirmed by MRI, asymptomatic, with or without prior local therapy; ECOG score of 0-1.
• To assess cohort D for IR of subjects with locally confirmed BRAF V600 D/E/K/R cutaneous melanoma with metastases to the brain confirmed by MRI, symptomatic; with or without prior local therapy; ECOG score of 0-2.
• To assess Cohorts A, B, C and D for Disease Control for intracranial, extracranial and overall response (IDC, EDC and ODC respectively)
• To assess Cohorts A, B, C and D for extracranial response rate (ER)
• To assess Cohorts A, B, C and D for overall response rate (OR)
For further information please view section 2 of the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is ≥ 18 years of age
2. Has signed written informed consent.
3. ECOG score of 0-1 for Cohorts A, B and C and ECOG score of 0-2 for Cohort D.
4. Histologically confirmed via CLIA-certified assay for cutaneous metastatic melanoma (Stage IV; See Appendix 1 for staging), and determined to be V600 E, K, D or R. BRAF V600E mutation status for the subjects in Cohort A will be determined prospectively by the THxIDTM BRAF assay conducted in a central reference laboratory. Subjects in cohorts B, C and D are eligible to enroll based on local test results. Certified local test results will be subjected to retrospective central confirmation by a GSK designated assay.
5. May be systemic naïve or received up to two previous systemic treatment regimens for metastatic melanoma including chemo-, cytokine-, immune-, biological- and vaccine therapy. Prior TMX for brain metastases and adjuvant IFN are acceptable and does not count toward the two previous systemic treatment regimens.
6. Must be able to undergo MRI and have at least one measurable intracranial lesion for which all of the following criteria have to be met:
a. Previously untreated or progressive according to RECIST 1.1 (>/= 20% increase in longest diameter on baseline scan) after previous local therapy
b. Largest diameter of >/= 0.5cm diameter but </= 4cm as determined by contrast-enhanced MRI.
c. for target lesions with diameter of > 0.5cm but <= 1 cm documented measurement by a neurologist is required.
d. For all lesions with a diameter of ≥ 3cm but <= 4 cm documented measurement by a neuroradiologist is required.
7. All prior anti-cancer treatment related toxicities (except alopecia) must be <= Grade 1 according to Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute (NCI 2009) at the time of entry
a.http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
8. 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.
9. Must have adequate organ function as defined in Table 2 please view the protocol.
10. Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment.
NOTE: Oral contraceptives are not reliable due to potential drug-drug interaction with dabrafenib
11. French subjects: 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 |
1. Neurological symptoms related to brain metastasis except for Cohort D where subjects can be symptomatic.
2. Prior treatment with any BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, or any BRAF mutant selective agent) or any MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119).
3. Anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) or investigational anti-cancer therapy within 3 weeks, or chemotherapy without delayed toxicity within the 2 weeks of starting study treatment. (Note: Ipilimumab treatment must end at least 8 weeks prior to dosing.
4. Treatment with stereotactic radiosurgery within 14 days prior to start of study treatment, or treatment with whole-brain radiation within 28 days prior to study treatment.
5. Any presence of leptomeningeal disease or any parenchymal brain metastasis >4.0 cm in diameter.
6. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is longer, prior to dosing.
7. Current or expected use of a prohibited medication
8. 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) or subjects with a history of completely resected non-melanoma skin cancer.
9. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the investigator, could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
10. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted).
11. Acute infection requiring intravenous antibiotics.
12. 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; See Appendix 4
c. A history or evidence of current clinically significant uncontrolled arrhythmias;
Exception: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible.
d. A history (within 6 months prior dosing) 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.
f. Treatment refractory hypertension defined as a blood pressure of systolic >140mmHg and/ or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive 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.
13. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (RPED) including:
a. Presence of predisposing factors to RVO or RPED (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 RPED such as:
i. Evidence of new optic disc cupping;
ii. Evidence of new visual field defects on automated perimetry;
iii. Intraocular pressure >21 mm Hg 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. Pregnant or nursing females.
16. Interstitial lung disease or pneumonitis
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • IR is defined as the proportion of subjects with a confirmed intracranial complete response (CR) or partial response (PR) as per investigator assessment using modified RECIST 1.1 guidelines [Eisenhauer, 2009]. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Intracranial will be assessed at baseline, Week 4, Week 8, and every 8 weeks thereafter. After Week 40, disease assessments may be performed every 12 weeks
|
|
| E.5.2 | Secondary end point(s) |
• IR is defined as the percentage of subjects with a confirmed intracranial complete response (CR) or partial response (PR) as per investigator assessment using modified RECIST 1.1 guidelines [Eisenhauer, 2009].
• Intracranial Disease Control (IDC) is defined as CR+PR+SD for intracranial, extracranial, and overall disease control
• Extracranial response (ER), defined as the percentage of subjects with a best extracranial response of a confirmed CR or PR by investigator assessment using modified RECIST 1.1
• Overall response (OR), defined as the percentage of subjects with a best overall confirmed response of CR or PR by investigator assessment.
• Duration of intracranial, extracranial and overall response (DIR, DER and DOR), defined as the time from first documented evidence of CR or PR until time of first documented intracranial, extracranial and overall disease progression.
• PFS, defined as the interval between first dose and the earliest date of disease progression or death due to any cause
• Overall survival (OS), defined as the time from first dose until death due to any cause.
• Assessment of safety of dabrafenib and trametinib measured by the frequency and severity of adverse events, skin assessments, laboratory abnormalities, vital signs, and assessment data (12-lead electrocardiograms (ECG), echocardiograms, and clinical monitoring/observation including neurological examination).
Exploratory endpoints:
• Tumour DNA, RNA, and protein content, other tumour tissue aberrations, clinical outcome and their association of the mutation profile with tumour response.
• BRAF and other cancer gene mutations in cfDNA, cfDNA burden and their association with tumour response
• Germline genetic variants and their association with safety measures (as listed under secondary endpoints), , and with tumour response. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Intracranial and extracranial disease will be assessed at baseline, Week 4, Week 8, and every 8 weeks thereafter. After Week 40, disease assessments may be performed every 12 weeks. |
|
| 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 | No |
| 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 | Yes |
| 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
| 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 | 26 |
| 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 |
| Canada |
| France |
| Italy |
| Australia |
| Germany |
| Spain |
| 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 |
Print
