Subjects with BRAF Mutation-Positive Melanoma that has Metastasized to the Brain MedDRA version: 14.1 Level: LLT Classification code 10027481 Term: Metastatic melanoma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Tafinlar
Product Name: Tafinlar
Product Code: GSK1218436
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: DABRAFENIB
CAS Number: 1195765-45-7
Current Sponsor code: GSK2118436
Other
Sponsors
GlaxoSmithKline, S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
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 0.5cm but =65 years) yes F.1.3.1 Number of subjects for this age range 24
Exclusion criteria
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: - 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.;Main Objective: 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).;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].;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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.;Timepoint(s) of evaluation of this end point: Intracranial and extracranial disease will be assessed at baseline, Week 4, Week 8, and ev | — |
Countries
Australia, Canada, France, Germany, Italy, Spain, United States
Contacts
Public ContactClinical Trials HelpDesk
GlaxoSmithKline Reseacrh & Development Ltd
Outcome results
None listed