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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02034110
Recruitment Status : Active, not recruiting
First Posted : January 13, 2014
Last Update Posted : January 10, 2020
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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 or disease Intervention/treatment Phase
Cancer Drug: Dabrafenib Drug: Trametinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 206 participants
Intervention Model: Parallel Assignment
Intervention Model Description: 9 indications
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 12, 2014
Estimated Primary Completion Date : July 26, 2020
Estimated Study Completion Date : July 26, 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Dabrafenib + Trametinib
Subjects will receive Dabrafenib 150 mg twice daily orally plus Trametinib 2 mg once daily orally on a continuous basis. Dabrafenib will be administered under fasted conditions, either 1 hour (hr) before or 2 hours (hrs) after a meal with approximately 200 mL of water with an interval of 12 hours. Trametinib will be administered under fasted conditions, either 1 hr before or 2 hrs after a meal with approximately 200 mL of water. Subjects will take their dose of Trametinib concurrently with the morning dose of Dabrafenib. A treatment cycle is 28 days in duration. Subjects will continue treatment until an unacceptable toxicity, disease progression, or death occurs.
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.

Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Possibly up to Week 208 ]
    To determine the ORR as measured radiographically via Response Evaluation Criteria in Solid tumors (RECIST) version 1.1 for solid tumor histologies or established response criteria for specific hematologic malignancies.

Secondary Outcome Measures :
  1. Duration of response [ Time Frame: From the time of first documented evidence of CR or PR until the first documented sign of disease progression or death (approximately up to Week 208) ]
    Duration of response is defined as the subset of subjects who show a confirmed clinical response (CR) or partial response (PR), the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.

  2. Investigator-assessed Progression-free survival (PFS) [ Time Frame: Possibly up to Week 208 ]
    PFS is defined as the time from the date of enrollment to the earliest date of progression or death.

  3. Overall Survival (OS) [ Time Frame: Until death or lost to follow-up (approximately up to Week 208) ]
    OS is defined as the time from the date of enrollment to the date of death due to any cause.

  4. Change from baseline in physical examination findings [ Time Frame: Possibly up to Week 208 ]
    Examination will include assessments of the head and neck, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, extremities and genitalia. Height (measured only at Screening) and weight will be measured and recorded. Complete physical examinations will also include thorough rectal and genitourinary (pelvic) examinations to assess secondary malignancies.

  5. Change from baseline in vital signs [ Time Frame: Possibly up to Week 208 ]
    Vital sign measurements will include systolic and diastolic blood pressure, temperature, pulse rate and respiratory rate

  6. Number of subjects with Adverse events (AEs) [ Time Frame: Possibly up to Week 208 ]
    AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  7. Change from baseline in laboratory values [ Time Frame: Possibly up to Week 208 ]
    Laboratory assessments include haematology, clinical chemistry, urinalysis, coagulation and histology-specific tests

  8. Change from baseline in cardiac assessments [ Time Frame: Possibly up to Week 208 ]
    Cardiac assessments include Electrocardiogram (ECG) and Echocardiograms (ECHOs)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02034110

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Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals Identifier: NCT02034110    
Other Study ID Numbers: 117019
2013-001705-87 ( EudraCT Number )
CDRB436X2201 ( Other Identifier: Novartis )
First Posted: January 13, 2014    Key Record Dates
Last Update Posted: January 10, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
solid tumors
BRAF V600E mutation
Additional relevant MeSH terms:
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Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action