Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma
Condition: Cancer; Melanoma
MeSH terms: Melanoma
Intervention: Dabrafenib; Trametinib
Intervention description: Dabrafenib will be provided as 50 mg and 75 mg capsules. Each capsule will contain 50 mg or 75 mg of free base (present as the mesylate salt); Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets. Each tablet will contain 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)
Intervention MeSH terms: Trametinib; Dabrafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 77.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: melanoma; dabrafenib; trametinib; malignant skin cancer; skin cancer; BRAF V600 Mutation-Positive Melanoma

Summary:

      This was a single-arm, open-label, multi-center, Phase II study to evaluate dabrafenib and
      trametinib combination therapy in subjects with BRAF V600 mutation-positive, unresectable or
      metastatic Acral lentiginous or cutaneous melanoma. This study evaluated the objective
      response rate (ORR), progression free survival (PFS), duration of response, overall survival
      (OS), safety and efficacy, to assess steady state (all subjects) exposure to dabrafenib,
      dabrafenib metabolites, and trametinib and characterize the population pharmacokinetics (PK)
      and pharmacodynamics (PD) of dabrafenib and trametinib. Enrolled subjects were administered
      dabrafenib 150 milligram (mg) orally twice daily and trametinib 2 mg orally once daily.
      Treatment continued until disease progression, death, unacceptable toxicity, or withdrawal of
      consent, or study closure. After treatment discontinuation, subjects were followed for
      survival and disease progression as applicable.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed written informed consent, which includes compliance with the requirements and
             restrictions listed in the consent form.

          -  >=18 years of age.

          -  Histologically confirmed acral lentiginous or cutaneous melanoma that is either Stage
             IIIC (unresectable) or Stage IV (metastatic), and BRAF V600 mutation-positive. The
             test was to have been conducted at a designated central laboratory.

          -  Measurable disease (i.e., present with at least one measurable lesion) by RECIST
             version1.1.

          -  Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group
             (ECOG) scale.

          -  All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
             values) must be <=Grade 1 according to the Common Terminology Criteria for Adverse
             Events version 4 (CTCAE version 4.0) at the time of enrolment.

          -  Able to swallow and retain oral medication and must not have had any clinically
             significant gastrointestinal abnormalities that may alter absorption such as
             malabsorption syndrome or major resection of the stomach or bowels.

          -  Women of child-bearing potential must have had a negative serum pregnancy test within
             14 days of first dose of study treatment and agree to use effective contraception,
             from 14 days prior to enrolment, throughout the treatment period and for 4 months
             after the last dose of study treatment.

          -  Adequate baseline organ function as defined below: Absolute Neutrophil Count:>= 1.2 ×
             10^9/liter (L); Hemoglobin: >=9 grams (g)/deciliter (dL); Platelet count: >=100 x
             10^9/L; Prothrombin Time/International Normalized Ratio (INR) (Subjects receiving
             anticoagulation treatment may be allowed to participate with INR established within
             the therapeutic range prior to enrolment) and Partial Thromboplastin Time: <=1.5 x
             Upper Limit of Normal (ULN); Albumin: >=2.5 g/dL; Total bilirubin: <=1.5 x ULN;
             Aspartate aminotransferase and Alanine aminotransferase: <=2.5 x ULN; Calculated
             creatinine clearance (Calculate creatinine clearance using standard Cockcroft-Gault
             formula): >=50 milliliter (mL)/ minute (min); Left Ventricular Ejection Fraction
             (LVEF) (ECHO scans must be used throughout the study) : >= Lower limit of normal (LLN)
             by ECHO.

          -  Subjects with East Asian origin.

        Exclusion Criteria:

          -  Primary mucosal or ocular melanoma.

          -  Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib,
             vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not
             limited to trametinib, AZD6244, and RDEA119).

          -  Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
             biologic anti-cancer therapy, or immuno anti-cancer therapy within 21 days prior to
             enrolment /or daily or weekly chemotherapy without the potential for delayed toxicity
             within 14 days prior to enrolment. (Note: Ipilimumab, pembrolizumab and nivolumab
             treatment must ended at least 8 weeks prior to enrollment).

          -  Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days),
             whichever is shorter, prior to enrolment. (Note: in case ipilimuamb, pembrolizmab and
             nivolumab are investigational drug in the regions and countries, and in case of PD-L1
             antibody, these investigational treatment must have ended at least 8 weeks prior to
             enrollment ).

          -  Current use of a prohibited medication.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study treatments, their excipients, and/or dimethyl
             sulfoxide (DMSO).

          -  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).

          -  Leptomeningeal or brain metastases or metastases causing spinal cord compression that
             were: symptomatic or untreated or not stable for 3 months (must be documented by
             imaging) or requiring corticosteroids. Subjects that were on a stable dose of
             corticosteroids >1 month or on replacement dose only, or have been off of
             corticosteroids for at least 2 weeks can be enrolled with approval of the medical
             monitor. Subjects must also have been off of enzyme-inducing anticonvulsants for >4
             weeks.

          -  History of malignancy other than disease under study within 3 years of study enrolment
             with exceptions of subjects with a history of completely resected non-melanoma skin
             cancer, or subjects with indolent second malignancies were eligible only after the
             approval of the sponsor's medical monitor.

          -  History of malignancy with confirmed activating RAS mutation at any time. Note:
             Prospective RAS testing was not required. However, if the results of previous RAS
             testing were known, they must have been used in assessing eligibility

          -  Any serious or unstable pre-existing medical conditions (aside from malignancy
             exceptions specified above), psychiatric disorders, or other conditions that could
             have interfered with the subject's safety, obtaining informed consent, or compliance
             with study procedures.

          -  A history or evidence of cardiovascular risk including any of the following: Current
             LVEF < Institutional LLN; A QTc interval corrected for heart rate >=480 millisecond
             (msec) (using Bazett's formula); A history or evidence of current clinically
             significant uncontrolled arrhythmias. Clarification: Subjects with atrial fibrillation
             controlled for >30 days prior to dosing are eligible; A history of acute coronary
             syndromes (including myocardial infarction or unstable angina), coronary angioplasty,
             or stenting within 6 months prior to randomization; A history or evidence of current
             >=Class II congestive heart failure as defined by the New York Heart Association
             (NYHA) guidelines; Patients with intra-cardiac defibrillators; Treatment refractory
             hypertension defined as a blood pressure of systolic >140 millimeters of mercury
             (mmHg) and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive
             therapy; Known cardiac metastases; 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 have been entered in study.

          -  Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia,
             hypocalcaemia determined by blood chemistry), long QT syndrome or taking medicinal
             products known to prolong the QT interval.

          -  A history or current evidence of retinal vein occlusion (RVO) .

          -  Pregnant or nursing females.

          -  History of or current diagnosis of interstitial lung disease or pneumonitis.