This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in
combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid
cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell
tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO)
Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and
adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. This study is
designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with
oral Trametinib in subjects with rare BRAF V600E mutated cancers. Subjects will need to have
a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status.
Only subjects with histologically confirmed advanced disease and no available standard
treatment options will be eligible for enrollment. Subjects will undergo screening
assessments within 14 days (up to 35 days for ophthalmology exam, echocardiogram or disease
assessments) prior to the start of treatment to determine their eligibility for enrollment in
- Signed, written informed consent.
- Sex: male or female.
- Age: >=18 years of age at the time of providing informed consent.
- Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2.
- Must have advanced disease and no standard treatment options as determined by
locally/regionally available standards of care and treating physician's discretion
- Must have a a BRAF V600E mutation-positive tumor as confirmed by an approved local
laboratory or a sponsor designated central reference laboratory. All subjects must
provide an archived or fresh tumor sample (for solid tumors) or a fresh BM aspirate
and peripheral blood sample (for HCL and MM) for confirmation testing of the BRAF
V600E mutation by a sponsor designated central reference laboratory using a sponsor
- Able to swallow and retain orally administered medication. NOTE: Subject should not
have any clinically significant gastrointestinal (GI) abnormalities that may alter
absorption such as malabsorption syndrome or major resection of the stomach or bowels.
For example, subjects should have no more than 50% of the large intestine removed and
no sign of malabsorption (i.e., diarrhea).NOTE: If clarification is needed as to
whether a condition will significantly affect the absorption of study treatments,
contact the GSK Medical Monitor.
- Female Subjects of Childbearing Potential: Subjects must have a negative serum
pregnancy test within 7 days prior to the first dose of study treatment and agrees to
use effective contraception, throughout the treatment period and for 4 months after
the last dose of study treatment.
- French subjects: In France, a subject will be eligible for inclusion in this study
only if either affiliated to or a beneficiary of a social security category
- Prior treatment with: BRAF and/or MEK inhibitor(s); anti-cancer therapy (e.g.,
chemotherapy with delayed toxicity, immunotherapy, biologic therapy or chemoradiation)
within 21 days or prior nitrosourea or mitomycin C containing therapy within 42 days
prior to enrollment and/or prior daily or weekly chemotherapy or biologic therapy
without the potential for delayed toxicity within 14 days prior to enrolment or prior
nvestigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to
- History of malignancy with confirmed activating RAS mutation at any time. Prospective
RAS testing is not required. However, if the results of previous RAS testing are
known, then those results must be used in assessing eligibility.
- Prior radiotherapy less than 14 days prior to enrollment, except for WHO Grade 1 4
glioma (radiotherapy is not permitted within 3 months prior to enrollment) and ATC
(radiotherapy is not permitted within 7 days prior to enrollment). Treatment-related
AEs must have resolved prior to enrollment.
- Prior major surgery less than 14 days prior to enrollment. Any surgery-related AE(s)
must have resolved prior to enrollment
- Prior solid organ transplantation or allogenic stem cell transplantation (ASCT).
However, previous autologous BM transplant (ABMT) or autologous peripheral blood stem
cell transplant (PBSCT) is permitted.
- History of another malignancy. Subjects with another malignancy are eligible if: (a)
disease-free for 3 years, or (b) have a history of completely resected non-melanoma
skin cancer, and/or (c) have an indolent second malignancy(ies).
- Presence of brain metastases (except for subjects in the WHO Grade 1 or 2 or 3 or 4
glioma histology cohorts) that are symptomatic or untreated or not stable for >=3
months (must be documented by imaging) or requiring corticosteroids. Subjects on a
stable dose of corticosteroids >14 days and have not required treatment with
enzyme-inducing anticonvulsants for >30 days prior to enrollment can be enrolled with
approval of the Medical Monitor
- Presence of symptomatic or untreated leptomeningeal or spinal cord compression.
Subjects who have been previously treated for these conditions and have stable CNS
disease (documented by consecutive imaging studies) for >60 days, are asymptomatic and
currently not taking corticosteroids, or have been on a stable dose of corticosteroids
for at least 30 days prior to enrollment, are permitted
- Presence of interstitial lung disease or pneumonitis
- Presence of any unresolved >=Grade 2 (per Common Terminology Criteria for Adverse
Events [CTCAE] version 4.0) toxicity from previous anti-cancer therapy at the time of
enrollment, except alopecia or Grade 2 anemia. Subjects with MM who have ≤Grade 2
peripheral neuropathy (per CTCAE v4.0) are permitted.
- Presence of any serious and/or unstable pre-existing medical disorder, psychiatric
disorder, or other conditions that could interfere with subject's safety, obtaining
informed consent or compliance to the study procedures
- History of retinal vein occlusion
- Clinically significant GI abnormalities that may alter absorption such as
malabsorption syndrome or major resection of the stomach or bowels. For example,
subjects should have no more than 50% of the large intestine removed and no sign of
malabsorption (i.e., diarrhea)
- History or evidence of cardiovascular risk including any of the following: Acute
coronary syndromes (including myocardial infarction and unstable angina), coronary
angioplasty, or stenting within 6 months prior to enrolment; clinically significant
uncontrolled arrhythmias; however, subjects with controlled atrial fibrillation for
>30 days prior to enrollment are eligible; class II or higher congestive heart failure
as defined by the New York Heart Association (NYHA) criteria; left ventricular
ejection fraction (LVEF) below the institutional LLN. If a LLN does not exist at an
institution, then use LVEF <50%; abnormal cardiac valve morphology (≥Grade 2)
documented by ECHO; however, subjects with Grade 1 abnormalities (i.e., mild
regurgitation/stenosis) may be entered on study but subjects with moderate valvular
thickening should NOT be enrolled; corrected QT (QTc) interval for heart rate using
Bazett-corrected QT interval (QTcB) >=480 msec; intracardiac defibrillator;
treatment-refractory hypertension defined as a blood pressure (BP) >140/90 mmHg which
may not be controlled by anti-hypertensive medication(s) and/or lifestyle
- Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
result within 3 months prior to first dose of study treatment. Subjects with positive
Hepatitis C antibody due to prior exposure can be enrolled, only if a confirmatory
negative Hepatitis C RNA polymerase chain reaction (PCR) test is obtained.
- Current use of prohibited medication(s) or requirement for prohibited medications
during study as per the study protocol. Use of anticoagulants such as warfarin is
permitted; however, international normalization ratio (INR) must be monitored
according to local institutional practice.
- Clinically significant known immediate or delayed hypersensitivity reaction or
idiosyncrasy to drugs chemically related to study treatment, or excipients, or to
dimethyl sulfoxide (structural component of dabrafenib).
- Pregnant, lactating or actively breastfeeding female subjects