Open-Labeled Study of Dabrafenib plus Trametinib in Subjects with BRAF Mutation-Positive Melanoma that has Metastasized to the Brain.
- Conditions
- Subjects with BRAF Mutation-Positive Melanoma that has Metastasized to the BrainMedDRA version: 14.1Level: LLTClassification code 10027481Term: Metastatic melanomaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]
- Registration Number
- EUCTR2013-003452-21-ES
- Lead Sponsor
- GlaxoSmithKline, S.A.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 120
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 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 96
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 24
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 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 b
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method