Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers
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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. |
| ClinicalTrials.gov Identifier: NCT02034110 |
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Recruitment Status :
Completed
First Posted : January 13, 2014
Last Update Posted : June 10, 2022
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Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
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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 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 206 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group 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 |
| Actual Primary Completion Date : | December 10, 2021 |
| Actual Study Completion Date : | December 10, 2021 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Dabrafenib
Dabrafenib is a 150 mg twice daily capsule administered orally on a continuous basis.
Other Names:
Drug: Trametinib Trametinib is a 2 mg once daily tablet administered orally on a continuous basis.
Other Names:
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Primary Outcome Measures :
- Overall Response Rate (ORR) [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (Interim Analysis cut-off date = 14-Sep-2020) ]Overall Response Rate (ORR) is defined as the percentage of participants with a confirmed overall response by investigator assessment as defined by the pre-specified response criteria for the disease type (RECIST v1.1, RANO, Consensus criteria for HCL and Multiple Myeloma). Specifically, ORR = (number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
Secondary Outcome Measures :
- Duration of Response (DoR) [ Time Frame: From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 78 months (Interim Analysis cut-off date = 14-Sep-2020) ]For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) is defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first.
- Progression Free Survival (PFS) based on Local Investigator assessment [ Time Frame: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 78 months (Interim Analysis cut-off date = 14-Sep-2020) ]Progression Free Survival (PFS) is defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject does not have a documented date of progression or death, PFS will be censored at the date of the last adequate assessment.
- Overall Survival (OS) [ Time Frame: From study treatment start date until date of of death from any cause, assessed up to 78 months (Interim Analysis cut-off date = 14-Sep-2020) ]Overall Survival (OS) is defined as the time from first dose until death due to any cause. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis.
- Incidence of Adverse events (AEs) [ Time Frame: From study treatment start date till 30 days safety follow-up, assessed up to 78 months (Interim Analysis cut-off date = 14-Sep-2020) ]The distribution of adverse events (AE) will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs) through the monitoring of relevant clinical and laboratory safety parameters.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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 ClinicalTrials.gov identifier (NCT number): NCT02034110
Locations
Hide 52 study locations
| United States, Arkansas | |
| Novartis Investigative Site | |
| Little Rock, Arkansas, United States, 72205 | |
| United States, California | |
| Novartis Investigative Site | |
| Santa Monica, California, United States, 90404 | |
| United States, Maryland | |
| Novartis Investigative Site | |
| Bethesda, Maryland, United States, 20892 | |
| United States, Massachusetts | |
| Novartis Investigative Site | |
| Boston, Massachusetts, United States, 02114 | |
| Novartis Investigative Site | |
| Boston, Massachusetts, United States, 02215 | |
| United States, New York | |
| Novartis Investigative Site | |
| New York, New York, United States, 10016 | |
| United States, Tennessee | |
| Novartis Investigative Site | |
| Nashville, Tennessee, United States, 37203 | |
| United States, Texas | |
| Novartis Investigative Site | |
| Houston, Texas, United States, 77030 | |
| Austria | |
| Novartis Investigative Site | |
| Innsbruck, Austria, 6020 | |
| Novartis Investigative Site | |
| Linz, Austria, 4010 | |
| Novartis Investigative Site | |
| Salzburg, Austria, A-5020 | |
| Novartis Investigative Site | |
| Wien, Austria, 1090 | |
| Belgium | |
| Novartis Investigative Site | |
| Jette, Belgium, 1090 | |
| Canada, Ontario | |
| Novartis Investigative Site | |
| Toronto, Ontario, Canada, M5G 2M9 | |
| Denmark | |
| Novartis Investigative Site | |
| Koebenhavn Oe, Denmark, 2100 | |
| France | |
| Novartis Investigative Site | |
| Bordeaux Cedex, France, 33076 | |
| Novartis Investigative Site | |
| Caen Cedex 9, France, 14 033 | |
| Novartis Investigative Site | |
| Dijon Cedex, France, 21079 | |
| Novartis Investigative Site | |
| Lille Cedex, France, 59020 | |
| Novartis Investigative Site | |
| Lyon cedex 03, France, 69437 | |
| Novartis Investigative Site | |
| Nantes cedex 1, France, 44093 | |
| Novartis Investigative Site | |
| Saint-Herblain, France, 44805 | |
| Novartis Investigative Site | |
| Strasbourg Cedex, France, 67091 | |
| Novartis Investigative Site | |
| Toulouse Cedex 9, France, 31059 | |
| Novartis Investigative Site | |
| Villejuif Cedex, France, 94805 | |
| Germany | |
| Novartis Investigative Site | |
| Freiburg, Baden-Wuerttemberg, Germany, 79106 | |
| Novartis Investigative Site | |
| Heidelberg, Baden-Wuerttemberg, Germany, 69120 | |
| Novartis Investigative Site | |
| Mannheim, Baden-Wuerttemberg, Germany, 68167 | |
| Novartis Investigative Site | |
| Tuebingen, Baden-Wuerttemberg, Germany, 72076 | |
| Novartis Investigative Site | |
| Berlin, Germany, 13353 | |
| Novartis Investigative Site | |
| Hamburg, Germany, 20246 | |
| Italy | |
| Novartis Investigative Site | |
| Roma, Lazio, Italy, 00128 | |
| Novartis Investigative Site | |
| Milano, Lombardia, Italy, 20132 | |
| Novartis Investigative Site | |
| Milano, Lombardia, Italy, 20133 | |
| Novartis Investigative Site | |
| Milano, Lombardia, Italy, 20141 | |
| Novartis Investigative Site | |
| Verona, Veneto, Italy, 37134 | |
| Japan | |
| Novartis Investigative Site | |
| Chiba, Japan, 277-8577 | |
| Novartis Investigative Site | |
| Tokyo, Japan, 104-0045 | |
| Korea, Republic of | |
| Novartis Investigative Site | |
| Seoul, Korea, Republic of, 06273 | |
| Novartis Investigative Site | |
| Seoul, Korea, Republic of, 110-744 | |
| Novartis Investigative Site | |
| Seoul, Korea, Republic of, 135-710 | |
| Novartis Investigative Site | |
| Seoul, Korea, Republic of, 138-736 | |
| Netherlands | |
| Novartis Investigative Site | |
| Amsterdam, Netherlands, 1066 CX | |
| Novartis Investigative Site | |
| Amsterdam, Netherlands, 1081 HV | |
| Novartis Investigative Site | |
| Nijmegen, Netherlands, 6525 GA | |
| Novartis Investigative Site | |
| Rotterdam, Netherlands, 3075 EA | |
| Novartis Investigative Site | |
| Utrecht, Netherlands, 3584 CX | |
| Norway | |
| Novartis Investigative Site | |
| Oslo, Norway, 0310 | |
| Spain | |
| Novartis Investigative Site | |
| Barcelona, Spain, 08035 | |
| Novartis Investigative Site | |
| Madrid, Spain, 28041 | |
| Novartis Investigative Site | |
| Pamplona, Spain, 31008 | |
| Sweden | |
| Novartis Investigative Site | |
| Stockholm, Sweden, SE-171 76 | |
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT02034110 |
| Other Study ID Numbers: |
117019 2013-001705-87 ( EudraCT Number ) CDRB436X2201 ( Other Identifier: Novartis ) BRF117019 ( Other Identifier: GlaxoSmithKline ) |
| First Posted: | January 13, 2014 Key Record Dates |
| Last Update Posted: | June 10, 2022 |
| Last Verified: | June 2022 |
| 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 www.clinicalstudydatarequest.com |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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solid tumors efficacy BRAF V600E mutation |
trametinib safety Dabrafenib |
Additional relevant MeSH terms:
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Trametinib Dabrafenib Antineoplastic Agents |
Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |