Phase II Biomarker Study Comparing the Combination of BRAF Inhibitor Dabrafenib With MEK Inhibitor Trametinib Versus the Combination After Monotherapy With Dabrafenib or Trametinib
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Dabrafenib; Trametinib
Intervention description: Dabrafenib will be provided as 50 mg and 75 mg capsules.; Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets.
Intervention MeSH terms: Trametinib; Dabrafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Diagnostic
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: dabrafenib; MEK; trametinib; BRAF; melanoma; Oncology

Summary:

      This is a three-arm, open-label, randomised Phase II study to evaluate whether the different
      sequencing of dabrafenib and trametinib monotherapies and the upfront combination has an
      impact on translational or clinical activity in subjects with BRAF mutant metastatic
      unresectable stage IIIc or IV melanoma. Both dabrafenib and trametinib have demonstrated
      clinical activity as monotherapies and in combination in BRAF-mutant melanoma. However,
      duration of responses seem to be limited due to acquired drug resistance. The goal of this
      protocol is to study the sequential effects of BRAF and MEK inhibition on skin, blood and
      tumour biomarkers and to study the correlation between biomarkers and response to treatment
      and intrapatient toxicity. Approximately 54 eligible subjects will be randomised in the ratio
      of 1:1:1 to one of the three treatment arms.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant with signed written informed consent;

          -  Participants of age >=18 years;

          -  Participants with histologically confirmed cutaneous melanoma that is either Stage
             IIIc (unresectable) or Stage IV (metastatic) (according to American Joint Committee on
             Cancer [AJCC] staging 7th edition).

          -  BRAF (proto-oncogene B-Raf) V600E/K mutation-positive confirmed by a local laboratory.

          -  Accessible melanoma tumours for biopsies (locally advanced primary melanoma or
             metastases)

          -  Measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST
             1.1) on not biopsied lesions.

          -  All prior anti-cancer treatment-related toxicities (except alopecia) must be <= Grade
             1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE
             version 4.0) at the time of randomisation.

          -  Able to swallow and retain orally administered medication and does not have any
             clinically significant gastrointestinal abnormalities that may alter absorption such
             as malabsorption syndrome or major resection of the stomach or bowels.

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to randomisation and agree to use effective contraception, throughout the
             treatment period, and for 4 months after the last dose of study treatment.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

          -  Adequate baseline organ function as defined : absolute neutrophil count >= 1.2 ×
             109/Liters (L); Haemoglobin >= 9 grams(g)/Deciliter (dL); Platelet count >= 75 x
             109/L; prothrombin time(PT)/ international normalized ratio (INR) and partial
             thromboplastin time (PTT) <= 1.5 x Upper limit of normal (ULN); Albumin >= 2.5 g/dL;
             Total bilirubin- <= 1.5 x ULN; aspartate aminotransferase(AST) and alanine
             transaminase (ALT) <= 2.5 x ULN; Calculated creatinine clearance >=50 mL/min; Left
             Ventricular Ejection fraction (LVEF) >= Lower limit of normal (LLN) by Echocardiogram
             (ECHO)

        Exclusion Criteria:

          -  Prior treatment with a BRAF or MEK inhibitor

          -  Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
             biologic therapy, or immunotherapy within 21 days prior to randomisation and/or daily
             or weekly chemotherapy without the potential for delayed toxicity within 14 days prior
             to randomisation.

          -  Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days),
             whichever is shorter, prior to randomisation

          -  Current use of a prohibited medication.

          -  Refusal of tumour and skin biopsies.

          -  History of another malignancy.

          -  Any serious and/or unstable pre-existing medical conditions (aside from malignancy
             exceptions specified above), psychiatric disorders, or other conditions that could
             interfere with the participant's safety, obtaining informed consent, or compliance
             with study procedures.

          -  Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
             Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection
             which will be allowed).

          -  A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

          -  Brain metastases are excluded unless: All known lesions were previously treated with
             surgery or stereotactic surgery (whole-brain radiation is not allowed unless given
             after definitive treatment with surgery or stereotactic surgery), OR Brain lesion(s),
             if still present, must be confirmed stable (i.e., no increase in lesion size) for >=
             12 weeks prior to randomisation (stability must be confirmed with two consecutive
             magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND
             Asymptomatic with no corticosteroid requirements for >= 4 weeks prior to
             randomisation, AND No enzyme inducing anticonvulsants for >= 4 weeks prior to
             randomisation.

          -  A history or evidence of cardiovascular risk including any of the following: LVEF <
             LLN; A QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480
             milliseconds (msec); A history or evidence of current clinically significant
             uncontrolled arrhythmias; Exception: Participants with atrial fibrillation controlled
             for > 30 days prior to randomisation are eligible; A history (within 6 months prior to
             randomisation) of acute coronary syndromes (including myocardial infarction or
             unstable angina), coronary angioplasty; A history or evidence of current >= Class II
             congestive heart failure as defined by the New York Heart Association (NYHA)
             guidelines; Treatment refractory hypertension defined as a blood pressure of systolic
             > 140 millimetres of mercury (mmHg) and/or diastolic > 90 mmHg which cannot be
             controlled by anti-hypertensive therapy; Participants with intra-cardiac
             defibrillators or permanent pacemakers; Known cardiac metastases; Abnormal cardiac
             valve morphology (>=grade 2) documented by echocardiogram (Participants with grade 1
             abnormalities [i.e., mild regurgitation/stenosis] can be entered on study).
             Participants with moderate valvular thickening should not be entered on study.

          -  A history or current evidence/risk of retinal vein occlusion (RVO) or central serous
             retinopathy (CSR) including: Presence of predisposing factors to RVO or CSR (e.g.,
             uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled
             diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
             Visible retinal pathology as assessed by ophthalmic examination that is considered a
             risk factor for RVO or CSR such as: Evidence of new optic disc cupping; Evidence of
             new visual field defects on automated perimetry; Intraocular pressure >21 mmHg as
             measured by tonography.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study treatments, their excipients, and/or dimethyl
             sulfoxide (DMSO).

          -  Pregnant or lactating females

          -  Interstitial lung disease or pneumonitis