Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers

A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare Cancers With Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib

ClinicalTrials.gov Identifier: NCT02034110

Novartis Reference Number: 117019

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

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 the study.

Condition 
Cancer
Phase 
Phase 2
Overall status 
Active, not recruiting
Enrollment count 
206 participants
Start date 
Mar 12, 2014
Completion date 
Aug 27, 2021
Gender 
All
Age(s)
18 Years and older (Adult, Older Adult)

Interventions

Drug
Dabrafenib
Dabrafenib is a 150 mg twice daily capsule administered orally on a continuous basis.
Drug
Trametinib
Trametinib is a 2 mg once daily tablet administered orally on a continuous basis.

Eligibility Criteria

Inclusion Criteria:

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 designated assay
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

Exclusion Criteria:

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 enrollment
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 modifications
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

Study Locations

United States
Novartis Investigative Site
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Little Rock, 72205
Arkansas
United States
Novartis Investigative Site
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Santa Monica, 90404
California
United States
Novartis Investigative Site
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Bethesda, 20892
Maryland
United States
Novartis Investigative Site
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Boston, 02114
Massachusetts
United States
Novartis Investigative Site
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Boston, 02215
Massachusetts
United States
Novartis Investigative Site
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New York, 10016
New York
United States
Novartis Investigative Site
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Nashville, 37203
Tennessee
United States
Novartis Investigative Site
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Houston, 77030
Texas
United States
Austria
Novartis Investigative Site
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Innsbruck, 6020
-
Austria
Novartis Investigative Site
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Linz, 4010
-
Austria
Novartis Investigative Site
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Salzburg, A-5020
-
Austria
Novartis Investigative Site
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Wien, 1090
-
Austria
Belgium
Novartis Investigative Site
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Jette, 1090
-
Belgium
Canada
Novartis Investigative Site
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Toronto, M5G 2M9
Ontario
Canada
Denmark
Novartis Investigative Site
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Koebenhavn Oe, 2100
-
Denmark
France
Novartis Investigative Site
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Bordeaux Cedex, 33076
-
France
Novartis Investigative Site
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Caen Cedex 9, 14 033
-
France
Novartis Investigative Site
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Dijon Cedex, 21079
-
France
Novartis Investigative Site
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Lille Cedex, 59020
-
France
Novartis Investigative Site
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Lyon cedex 03, 69437
-
France
Novartis Investigative Site
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Nantes cedex 1, 44093
-
France
Novartis Investigative Site
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Saint-Herblain, 44805
-
France
Novartis Investigative Site
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Strasbourg Cedex, 67091
-
France
Novartis Investigative Site
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Toulouse Cedex 9, 31059
-
France
Novartis Investigative Site
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Villejuif Cedex, 94805
-
France
Germany
Novartis Investigative Site
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Freiburg, 79106
Baden-Wuerttemberg
Germany
Novartis Investigative Site
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Heidelberg, 69120
Baden-Wuerttemberg
Germany
Novartis Investigative Site
-
Mannheim, 68167
Baden-Wuerttemberg
Germany
Novartis Investigative Site
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Tuebingen, 72076
Baden-Wuerttemberg
Germany
Novartis Investigative Site
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Berlin, 13353
-
Germany
Novartis Investigative Site
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Hamburg, 20246
-
Germany
Italy
Novartis Investigative Site
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Roma, 00128
Lazio
Italy
Novartis Investigative Site
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Milano, 20132
Lombardia
Italy
Novartis Investigative Site
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Milano, 20133
Lombardia
Italy
Novartis Investigative Site
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Milano, 20141
Lombardia
Italy
Novartis Investigative Site
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Verona, 37134
Veneto
Italy
Japan
Novartis Investigative Site
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Chiba, 277-8577
-
Japan
Novartis Investigative Site
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Tokyo, 104-0045
-
Japan
Korea, Republic of
Novartis Investigative Site
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Seoul, 06273
-
Korea, Republic of
Novartis Investigative Site
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Seoul, 110-744
-
Korea, Republic of
Novartis Investigative Site
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Seoul, 135-710
-
Korea, Republic of
Novartis Investigative Site
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Seoul, 138-736
-
Korea, Republic of
Netherlands
Novartis Investigative Site
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Amsterdam, 1066 CX
-
Netherlands
Novartis Investigative Site
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Amsterdam, 1081 HV
-
Netherlands
Novartis Investigative Site
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Nijmegen, 6525 GA
-
Netherlands
Novartis Investigative Site
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Rotterdam, 3075 EA
-
Netherlands
Novartis Investigative Site
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Utrecht, 3584 CX
-
Netherlands
Norway
Novartis Investigative Site
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Oslo, 0310
-
Norway
Spain
Novartis Investigative Site
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Barcelona, 08035
-
Spain
Novartis Investigative Site
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Madrid, 28041
-
Spain
Novartis Investigative Site
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Pamplona, 31008
-
Spain
Sweden
Novartis Investigative Site
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Stockholm, SE-171 76
-
Sweden

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