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Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02296996
Recruitment Status : Completed
First Posted : November 21, 2014
Last Update Posted : January 23, 2019
Information provided by (Responsible Party):
Bart Neyns, Universitair Ziekenhuis Brussel

Brief Summary:
Patients with BRAF V600 mutant advanced melanoma benefit from treatment with a BRAF-inhibitor (e.g. dabrafenib, vemurafenib) and from combination of a BRAF- and MEK-inhibitor (e.g. dabrafenib and trametinib). Following initial tumor regression, progression is diagnosed in a majority of patients treated with BRAF-inhibitor mono-therapy within the first 12-months of therapy. Various molecular mechanisms that underlie the development of resistance to treatment with a BRAF-inhibitor have been reported. These mechanisms do not include secondary mutations in the BRAF-gene and therefore resistance to BRAF-inhibition could potentially be reversible when selective pressure by BRAF-inhibition is withheld for a sufficient period of time of melanoma progression. This clinical trial protocol addresses the potential renewed anti-tumor activity of combined BRAF- and MEK inhibition with the combination of dabrafenib and trametinib in patients with unresectable AJCC stage III or - IV BRAF V600 mutant melanoma who are documented with progression of disease at least 12 weeks following the last day of dosing of a BRAFinhibitor containing treatment regimen.

Condition or disease Intervention/treatment Phase
Malignant Melanoma Drug: Dabrafenib + Trametinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Clinical Trial on the Combination of Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients With Advanced BRAF V600 Mutant Melanoma
Study Start Date : October 2014
Actual Primary Completion Date : December 2017
Actual Study Completion Date : December 2017

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Dabrafenib + trametinib
Single arm study with dabrafenib + trametinib combination therapy
Drug: Dabrafenib + Trametinib

Primary Outcome Measures :
  1. Overall response rate [ Time Frame: Participants will be monitored until progression, with an expected average of 6 months ]

Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: Participants will be monitored until progression, with an expected average of 6 months ]
  2. Overall Survival [ Time Frame: 2 years ]
  3. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Participants will be monitored until progression, with an expected average of 6 months ]
    Detect adverse events

Other Outcome Measures:
  1. Tumour-specific cfDNA levels [ Time Frame: Participants will be monitored until progression, with an expected average of 6 months ]
    To explore if tumor specific cfDNA levels can be used as a monitoring tool to detect early progression of disease

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 18 years of age and signed written informed consent.
  2. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive.
  3. Subjects must have failed at least two prior systemic anti-cancer treatments for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma that must have included:

    • Treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, and LGX818) and progression of disease per RECIST, version 1.1 [Eisenhauer, 2009] must have been documented during this treatment.
    • Treatment with ipilimumab (or an alternative experimental immunotherapy) and progression of disease per immune related response criteria [Wolchock Clin Cancer Res December 1, 2009 15; 7412] must have been documented during this treatment.
  4. Documented progression of disease per RECIST, version 1.1 [Eisenhauer, 2009]) or per immune related response criteria [Wolchock Clin Cancer Res December 1, 2009 15; 7412] if the latest systemic therapy administered was ipilimumab, an anti-PD1 or anti-PD-L1 therapy, or any other experimental immunotherapy.
  5. The presence of at least one measurable lesion per RECIST, version 1.1 [Eisenhauer, 2009]).
  6. Interval between the date of the last administration of prior therapy for melanoma and the date of recruitment:

    • > 12 weeks following the date of the last administration of a BRAF-inhibitor;
    • > 12 weeks following the date of the first administration and > 4 weeks following the date of the last administration of ipilimumab, or an anti-PD1, or anti-PD-L1 therapy;
    • > 4 weeks following the date of the last administration of chemotherapy (> 6 weeks in case of a nitrosurea or mitomycin C containing regimen);
    • > 4 weeks following major surgery or extensive radiotherapy.
  7. Subjects with ocular melanoma are not eligible.
  8. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 2) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute ( NCI,) 2009) at the time of recruitment.
  9. 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.
  10. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to recruitment and agree to use effective contraception, as defined in Section, throughout the treatment period, and for 4 months after the last dose of study treatment.
  11. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 [Oken, 1982]. Refer to Appendix 1 for details.
  12. Adequate baseline organ function as defined in Table 2.

Exclusion Criteria:

  1. Grade 4 or repetitive grade 3 adverse event(s) related to prior treatment with a BRAF- and/or MEK inhibitor.
  2. Any contra-indication for evaluation by whole body CT and MRI of the brain.
  3. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
  4. Current use of a prohibited medication as described in Section 6 or requires any of these medications during treatment.
  5. History of another malignancy, including any malignancy with confirmed activating RAS mutation. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility. 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 ago) not including malignancy with confirmed activating RAS mutation, or subjects with a history of completely resected non-melanoma skin cancer.
  6. 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.
  7. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
  8. Patients with progressive symptoms from active brain metastasis or in need of an increase in corticosteroids dose to control symptoms within 4 weeks prior to recruitment are excluded
  9. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment
  10. A history or evidence of cardiovascular risk including any of the following:

    • Current LVEF < LLN
    • A QT interval corrected for heart rate using the Bazett's formula (QTcB; Section ≥480 msec;
    • A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to recruitment are eligible.
    • A history (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty or stenting;
    • A history or evidence of current ≥Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines (Appendix 4);
    • 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;
    • Patients with intra-cardiac defibrillators;
    • 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.
  11. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the QT interval.
  12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
  13. Females who are pregnant or nursing.
  14. Interstitial lung disease or pneumonitis
  15. Patients with a prior history of central serous retinopathy or retinal vein occlusion are excluded. Patients with a preexisting major ocular pathology are not eligible.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02296996

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UZ Brussel
Brussels, Belgium, 1090
Sponsors and Collaborators
Universitair Ziekenhuis Brussel
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Principal Investigator: Neyns Bart, MD, PhD Universitair Ziekenhuis Brussel
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Bart Neyns, Bart Neyns, MD PhD, Universitair Ziekenhuis Brussel Identifier: NCT02296996    
Other Study ID Numbers: UZB-BN- 2013-001
First Posted: November 21, 2014    Key Record Dates
Last Update Posted: January 23, 2019
Last Verified: January 2019
Keywords provided by Bart Neyns, Universitair Ziekenhuis Brussel:
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action