Inclusion Criteria: Subjects eligible for enrolment in this study must meet all of the
- Provided written informed consent,
- Male or female >=18 years of age and able to swallow and retain orally administered
study treatment and does not have any clinically significant gastrointestinal (GI)
abnormalities that may alter absorption such as malabsorption syndrome or major
resection of the stomach and/or bowels.
- Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced
or metastatic BRAF V600E mutation positive CRC
- Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced
or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by
relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy,
defined as patients that derived benefit (disease control based on investigator
assessment for >6 months OR partial response [confirmed or unconfirmed] based on
RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then
subsequently progressed on therapy. The anti-EGFR therapy must have been the most
recent therapy and the patient must have progressed based on investigator assessment
within 3 months of screening. Acceptable prior anti-EGFR-containing therapies
include: a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b.
irinotecan/anti-EGFR combo after previously having disease progression (based on
investigator assessment) on an irinotecan-containing regimen
- Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation
positive advanced or metastatic colorectal cancer (CRC who are eligible to receive
fluoropyrimidine-containing chemotherapy regimen that have experienced documented
radiographic progression on one prior line of fluoropyrimidine-containing
chemotherapy (previous anti-EGFR therapy is excluded), Second-line for
advanced/metastatic disease, having failed or been intolerant to at least one regimen
of fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in
the advanced/metastatic setting. Enrollment in Part 3 may only occur following
confirmation of KRAS wild-type cancer.
- Archival tissue is required; if archival tissue is not available or found to not
contain tumor tissue, a fresh biopsy is required.
- Measurable disease per RECIST version 1.1.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Men with a female partner of childbearing potential must have either had a prior
vasectomy or agree to use one of the contraception methods listed in protocol.
- Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal
females with a documented tubal ligation or hysterectomy; or post-menopausal female
defined as 12 months of spontaneous amenorrhea to be verified with a
follicle-stimulating hormone (FSH) level >40 Milli-international units per milliliter
(MIU/mL) and estradiol level <40 picogram per milliliter (pg/mL). Child-bearing
potential and agrees to use one of the contraceptive methods listed in protocol.
- Female subjects must agree to use contraception from 7 days prior to the first dose
of study drug(s) until 6 months after the last dose of panitumumab, until 4 months
after the last dose of trametinib, or 4 weeks after the last dose of dabrafenib,
whichever is longer. Additionally, women of childbearing potential must have had a
negative serum pregnancy test within 7 days prior to the first dose of study drug(s).
- Adequate organ system function as defined in absolute neutrophil count greater than
or equal to 1.2X10^9/Liter (L), hemoglobin greater than or equal to 9 grams per
deciliter (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or
equal to 75 10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and
Partial Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal
(ULN); serum magnesium greater than or equal to the lower limit of normal (LLN);
albumin greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total
bilirubin less than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and
Alanine aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than
or equal to 1.5XULN or calculated creatinine clearance greater than or equal to
50mL/min; left ventricular ejection fraction (LVEF) greater than or equal to the LLN
by echocardiography (ECHO) or multigated acquisition scan (MUGA).
- Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible
for inclusion in this study only if either affiliated to, or a beneficiary of, a
social security category.
Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in
- History of prior malignancy, other than colorectal cancer.
- 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.
- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
per investigator's assessment).
- History of sensitivity to heparin or heparin-induced thrombocytopenia.
- Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or
- Prior exposure to a MEK inhibitor.
- Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF
- Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of
KRAS-mutation based on previous KRAS-testing. Note: Propsective KRAS testing is not
required. However, if the results of previous KRAS testing are known, they must be
used in assessing eligibility. KRAS testing will be performed retrospectively for
- Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody
- Received an investigational or approved anti-cancer drug within 4 weeks, or within 5
half-lives (whichever is shorter) of the first dose of study drug(s). At least 14
days must have passed between the last dose of prior investigational agent and the
first dose of study drug(s).
- Part 3: Received more than one prior anti-cancer therapy in the metastatic setting,
exclusive of previous adjuvant regimens. Previous investigational anti-cancer
therapy in the metastatic setting is prohibited.
- Current use of a prohibited medication or requirement to dose with any of these
medications during treatment with study drug(s).
- Known Hepatitis B, or Hepatitis C infection.
- Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first
dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose
of study drug(s).
- Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of
study drug(s). Chemotherapy regimens given continuously or on a weekly basis with
limited potential for delayed toxicity within 2 weeks prior to first dose of study
- Unresolved toxicity greater than National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer
therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory
values that are allowed per inclusion criteria.
- History of retinal vein occlusion (RVO).
- Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption, distribution, metabolism or excretion of drugs.
Previous colectomy is acceptable.
- Subjects with brain metastases are excluded, unless: All known lesions must be
previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s),
if present, must be confirmed stable (i.e., no increase in lesion size) for >=90 days
prior to first dose of study drug(s). This must be documented with two consecutive
MRI or CT scans using contrast, and Asymptomatic with no corticosteroids requirement
for >=30 days prior to first dose of study drug(s), and No enzyme-inducing
anticonvulsants for >=14 days prior to first dose of study drug(s). In addition, for
subjects that had brain metastases but currently have no evidence of disease (NED),
NED for >=12 weeks is required and must be confirmed by two consecutive MRI or CT
scans (using contrast) separated by >=6 weeks, prior to randomization. Enrollment of
a subject with brain metastases who meet the above criteria requires approval of a
GlaxoSmithKline (GSK) Medical Monitor.
- Psychological, familial, sociological or geographical conditions that do not permit
compliance with the protocol.
- 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);.History or evidence of current clinically significant
uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation
for >30 days prior to randomization are eligible. History of acute coronary syndromes
(including myocardial infarction and unstable angina), coronary angioplasty, or
stenting within 6 months prior to randomization. History or evidence of current >=
Class II congestive heart failure as defined by New York Heart Association (NYHA).
Treatment refractory hypertension defined as a blood pressure of systolic> 140
millimeter of mercury (mm Hg) and/or diastolic > 90 mm Hg which cannot be controlled
by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent
pacemakers; Known cardiac metastases
- Unstable pulmonary embolism, deep vein thrombosis, or other significant
arterial/venous thromboembolic event <=30 days before randomization. If on
anticoagulation, subject must be on stable therapeutic dose prior to randomization.
- Subjects with a history of pneumonitis or interstitial lung disease (ILD).
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drug(s) or their excipients.
- Pregnant or lactating female.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Uncontrolled diabetes or other medical condition that may interfere with assessment
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
Part 1: Plasma pharmacokinetics (PK) profile of dabrafenib, trametinib and panitumumab in combination dosing
Part 1: Response rate (CR +PR) of dabrafenib dosed orally in combination with panitumumab
Part 1 and Part 2: Progression free survival of subjects treated with dabrafenib dosed orally in combination with panitumumab
Part 1 and Part 2: Duration of response of dabrafenib dosed orally in combination with panitumumab
Part 1: Response rate (CR +PR) of trametinib dosed orally in combination with dabrafenib and panitumumab
Part 1 and Part 2: Progression free survival subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab
Part 1 and Part 2: Duration of response of trametinib dosed orally in combination with dabrafenib and panitumumab
Part 1, Part 2, Part 4A and Part 4B: Change in levels of proteins/ Ribonucleic acid (RNA) in pre- and post-dose tumor tissue
Part 2: Plasma pharmacokinetics profile of of dabrafenib and trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)
Part 2: Overall survival (OS) of subjects treated with dabrafenib dosed orally in combination with panitumumab
Part 2: OS of subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab
Part 3: Response rate (CR +PR) of dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy
Part 3: Duration of response to dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy
Part 3: OS of subjects treated with dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy
Part 3: To evaluate and compare the PFS of the trametinib/dabrafenib/panitumumab combination as compared to the dabrafenib/panitumumab combination
Part 3: Composite safety parameters including adverse events and changes in laboratory values, vital signs and dose interruptions, modifications and discontinuations
Part 4A: Plasma pharmacokinetics profile of trametinib and panitumumab after combination therapy
Part 4A: Response rate (CR +PR) of panitumumab/trametinib combination therapy in patient populations
Part 4A and Part 4B: Progression free survival of panitumumab/trametinib combination therapy in patient populations
Part 4A and Part 4B: Duration of response of panitumumab/trametinib combination therapy in patient populations
Part 4B Plasma pharmacokinetics profile of trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)
Part 4B Overall survival of response with trametinib dosed in combination with panitumumab