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Phase 1 Study of the BRAF Inhibitor Dabrafenib +/- MEK Inhibitor Trametinib in Combination With Ipilimumab for V600E/K Mutation Positive Metastatic or Unresectable Melanoma

Phase 1
18 Years
Open (Enrolling)
Solid Tumours

Thank you

Trial Information

Phase 1 Study of the BRAF Inhibitor Dabrafenib +/- MEK Inhibitor Trametinib in Combination With Ipilimumab for V600E/K Mutation Positive Metastatic or Unresectable Melanoma

Inclusion Criteria:

- Signed written informed consent

- Males and females >= 18 years of age

- Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable)
or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive
by the local laboratory. Subjects with ocular or mucosal melanoma are not eligible

- Measurable tumor by physical or radiographic examination

- Subjects must not have had more than 1 previous treatment regimen with chemotherapy,
interferon, or IL-2 for metastatic melanoma

- All prior anti-cancer treatment-related toxicities (except alopecia) must be <= Grade
1 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
at the time of enrollment

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Adequate baseline organ function as defined by: absolute neutrophil count (ANC) >=
1.2 × 109/L; Hemoglobin >= 9 g/dL; Platelet count >= 100 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) <= 2.0 x ULN;
Creatinine <=1.5 mg/mL; Left Ventricular Ejection fraction (LVEF) >= lower limit of
normal (LLN) by ECHO

- Women of childbearing potential must have a negative serum pregnancy test within 7
days prior to randomization and agree to use effective contraception, during the
study, and for 30 days after the last dose of study treatment

- Men with a female partner of childbearing potential must have either had a prior
vasectomy or agree to use effective contraception for at least 2 weeks prior to the
first dose of study treatment until 16 weeks after the last dose of study treatment
to allow for clearance of any altered sperm

- Able to swallow and retain orally administered study treatment 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

Exclusion Criteria:

- Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib,
vemurafenib, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to
trametinib, AZD6244, and RDEA119) or ipilimumab or any other agent targeting a T-cell
immunomodulatory pathway (including, but not limited to CTLA-4, PD-1, 4-1BB, OX40,
GITR, CD27, and CD28)

- Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily
or weekly chemotherapy without the potential for delayed toxicity within 14 days
prior to randomization

- 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

- A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency

- Brain metastasis are excluded unless

1. 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) AND

2. Brain lesion(s), if still present, must be confirmed stable (i.e., no increase
in lesion size) for >= 6 weeks prior to randomization (stability must be
confirmed with two consecutive magnetic resonance image (MRI) or computed
tomography (CT) scans with contrast, AND

3. Asymptomatic with no corticosteroid requirements for >= 4 weeks prior to
randomization, AND

4. No enzyme inducing anticonvulsants for >= 4 weeks prior to randomization

- A history or evidence of cardiovascular risk including any of the following

1. LVEF < LLN for the institution

2. A corrected QT interval >=480 msec (e.g. Bazett's formula [QTcB])

3. A history or evidence of current clinically significant uncontrolled arrhythmias
(exception: subjects with controlled atrial fibrillation for > 30 days prior to
randomization are eligible)

4. A history (within 6 months prior to first dose of study treatment) of acute
coronary syndromes (including myocardial infarction or unstable angina),
coronary angioplasty

5. A history or evidence of current >=Class II congestive heart failure as defined
by the New York Heart Association (NYHA)

6. Treatment refractory hypertension defined as systolic blood pressure >140
millimetres of mercury (mmHg) and/or diastolic blood pressure >90 mmHg which
cannot be controlled by antihypertensive therapy

7. Patients with intra-cardiac defibrillators

8. 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

- A history or current evidence/risk of retinal vein occlusion (RVO) or Central serous
retinopathy (CSR) including

1. 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

2. 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

- History of any of the following diseases: inflammatory bowel disease or any other
autoimmune bowel disease; systemic lupus erythematosus; rheumatoid arthritis; or any
autoimmune ocular diseases. Patients with active autoimmune disease or a history of
autoimmune disease other than those mentioned above must be approved by the GSK
medical monitor

- Active pneumonitis or interstitial lung disease

- Lactating female

- History of another malignancy (Exception: Subjects who have been disease-free for 3
years, or subjects with a history of completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible)

- Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures

- Any prohibited medication

- Administration of an investigational study treatment within 28 days or 5 half-lives,
whichever is longer, preceding the first dose of study treatment(s) in this study

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study treatments, their excipients, and/or dimethyl
sulfoxide (DMSO)

- Unwillingness or inability to follow the procedures outlined in the protocol

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of subjects with Adverse Events (AEs) to assess the safety of dabrafenib +/- trametinib when administered in combination with ipilimumab

Outcome Description:

AEs will be collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment

Outcome Time Frame:

Follow-up up to 6 months after last subject last dose

Safety Issue:


Principal Investigator

GSK Clinical Trials

Investigator Role:

Study Director

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

February 2013

Completion Date:

December 2014

Related Keywords:

  • Solid Tumours
  • BRAF V600E
  • Melanoma
  • V600K
  • Trametinib
  • Dabrafenib
  • Ipilimumab
  • Melanoma



GSK Investigational Site Germantown, Tennessee  38138