Open-Labeled Study of Dabrafenib plus Trametinib in Subjects with BRAF Mutation-Positive Melanoma that has Metastasized to the Brain.

Phase 1

• Conditions: Subjects with BRAF Mutation-Positive Melanoma that has Metastasized to the Brain; MedDRA version: 19.1Level: LLTClassification code 10027481Term: Metastatic melanomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

• Registration Number: EUCTR2013-003452-21-DE
• Lead Sponsor: ovartis Pharma Services AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2014-01-07
• Last Update Posted: 3 April 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 120

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 ALL cohorts 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 temozolomide for brain metastases and adjuvant interferon 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 d For all lesions with a diameter of >/= 3cm but 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 prior to enrollment and agree to use effective contraception, from 14 days prior to enrollment, throughout the treatment period, and for 4 months after the last dose of study treatment.
11. Subjects registered 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.
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

Exclusion Criteria

1. Neurological symptoms related to brain metastasis except for Cohort D where subjects can be symptomatic.
2. Prior treatment with a BRAF inhibitor or a MEK inhibitor.
3. Known ocular or primary mucosal melanoma
4. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, within the last 3 weeks, or chemotherapy without delayed toxicity within the last 2 weeks preceding the first dose of the combination. Prior systemic treatment in the adjuvant setting is allowed (same timelines as above). (Note: Ipilimumab treatment must end at least 8 weeks prior to enrollment.)
5. 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.
6. Any presence of leptomeningeal disease or any parenchymal brain metastasis >4.0 cm in diameter.
7. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is longer, prior to dosing.
8. Current or expected use of a prohibited medication
9. History of malignancy with confirmed activating RAS mutation at any time. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility.
10. History of malignancy other than disease under study within 3 years, of study enrolment with exceptions below. Exception: Subjects with a history of completely resected non-melanoma skin cancer, or subjects with indolent second malignancies are eligible.
11. 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.
12. A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted).
13. A history or evidence of cardiovascular risk including any of t3e 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;
Clarification: 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.
14. A history or current evidence of retinal vein occlusion (RVO)
15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/ or dimethyl sulfoxide (DMSO).
16. Pregnant or nursing females.
17. History of Interstitial lung dis

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified