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

• ClinicalTrials.gov Identifier: NCT02034110
• Recruitment Status: Completed
• First Posted: January 13, 2014
• Results First Posted: August 21, 2023
• Last Update Posted: August 21, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This was a Phase II, open-label, non-randomized, multi-center study of oral dabrafenib in combination with oral trametinib in subjects with rare cancers harboring the BRAF V600E mutation including anaplastic thyroid cancer (ATC), biliary tract cancer (BTC), gastrointestinal stromal tumor (GIST), low grade (WHO G1/G2) glioma (LGG), high grade (WHO G3/G4) glioma (HGG), non-seminomatous germ cell tumors (NSGCT) / non-germinomatous germ cell tumors (NGGCT), adenocarcinoma of the small intestine (ASI), hairy cell leukemia (HCL) and multiple myeloma (MM).

Condition or disease	Intervention/treatment	Phase
Cancer	Drug: Dabrafenib; Drug: Trametinib	Phase 2

Detailed Description:

This study was 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 needed 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 were eligible for enrollment. Subjects underwent 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. All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, withdrawal of consent or death. Once a subject discontinued treatment, a post-treatment follow-up visit was conducted within 28 days (+ 7 days) after the last dose of study treatment(s). Extended follow-up visits were conducted every 4 weeks (+/- 7 days) for the first 6 months and then every 3 months (+/- 14 days) thereafter. A subject was considered to have discontinued the study if the subject was lost to follow-up or withdrew consent or another reason existed that prevented additional data from being collected on the subject. A subject was considered to have completed the study at the time of death.

For each histology, up to 25 patients were planned to be enrolled in each of the 9 primary analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy. All planned histology cohorts enrolled at least one subject, with the exception of the germ cell tumor cohort. Enrolment in the study was closed in July 2018.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 206 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: 9 indications: anaplastic thyroid cancer (ATC), biliary tract cancer (BTC), gastrointestinal stromal tumor (GIST), low grade (WHO G1/G2) glioma (LGG), high grade (WHO G3/G4) glioma (HGG), non-seminomatous germ cell tumors (NSGCT)/non-germinomatous germ cell tumors (NGGCT), adenocarcinoma of the small intestine (ASI), hairy cell leukemia (HCL) and multiple myeloma (MM).
• 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

Arms and Interventions

Arm

Intervention/treatment

Experimental: Dabrafenib + Trametinib; Subjects received Dabrafenib 150 mg twice daily orally plus Trametinib 2 mg once daily orally on a continuous basis. Dabrafenib was 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 was administered under fasted conditions, either 1 hr before or 2 hrs after a meal with approximately 200 mL of water. Subjects took their dose of Trametinib concurrently with the morning dose of Dabrafenib. A treatment cycle was 28 days in duration. Subjects continued treatment until an unacceptable toxicity, disease progression, or death occurs.

Drug: Dabrafenib; A 150 mg twice daily capsule administered orally on a continuous basis.; Other Names: DRB436; GSK2118436; Drug: Trametinib; A 2 mg once daily tablet administered orally on a continuous basis.; Other Names: TMT212; GSK1120212

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) in the Anaplastic Thyroid Cancer (ATC) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
2. Overall Response Rate (ORR) in the Biliary Tract Cancer (BTC) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
3. Overall Response Rate (ORR) in the Gastrointestinal Stromal Tumor (GIST) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
4. Overall Response Rate (ORR) in the Adenocarcinoma of the Small Intestine (ASI) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
5. Overall Response Rate (ORR) in the Low Grade (WHO G1/G2) Glioma (LGG) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (response assessment criteria (CR, PR, and minor response [MR]) WHO Grade 1 and 2 Glioma) by investigator assessment as defined by response assessment for neuro-oncology (RANO). Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
6. Overall Response Rate (ORR) in the High Grade (WHO G3/G4) Glioma (HGG) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (updated response assessment criteria (CR, PR) WHO Grade 3 and 4 Glioma) by investigator assessment as defined by modified response assessment for neuro-oncology (RANO). Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
7. Overall Response Rate (ORR) in the Hairy Cell Leukemia (HCL) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with CR +/- minimal residual disease [MRD], PR by investigator assessment as defined by the Consensus Resolution Criteria adapted from the National Comprehensive Cancer Network (NCCN) guidelines. Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
8. Overall Response Rate (ORR) in the Multiple Myeloma (MM) Cohort [ Time Frame: From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21) ]
   Overall Response Rate (ORR) was defined as the percentage of participants with stringent complete response (sCR), CR, PR, very good partial response (VGPR) by investigator assessment as defined by the International Myeloma Working Group (IMWG) Uniform Response Criteria for 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 :

1. Duration of Response (DoR) in the Anaplastic Thyroid Cancer (ATC) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was 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. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
2. Duration of Response (DoR) in the Biliary Tract Cancer (BTC) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was 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. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
3. Duration of Response (DoR) in the Adenocarcinoma of the Small Intestine (ASI) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was 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. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
4. Duration of Response (DoR) in the Low Grade (WHO G1/G2) Glioma (LGG) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was 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. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
5. Duration of Response (DoR) in the High Grade (WHO G3/G4) Glioma (HGG) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was 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. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
6. Duration of Response (DoR) in the Hairy Cell Leukemia (HCL) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was 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. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
7. Duration of Response (DoR) in the Multiple Myeloma (MM) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was 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. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
8. Progression Free Survival (PFS) in the Anaplastic Thyroid Cancer (ATC) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   Progression Free Survival (PFS) was 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 did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
9. Progression Free Survival (PFS) in the Biliary Tract Cancer (BTC) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
   Progression Free Survival (PFS) was 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 did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
10. Progression Free Survival (PFS) in the Adenocarcinoma of the Small Intestine (ASI) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
    Progression Free Survival (PFS) was 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 did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
11. Progression Free Survival (PFS) in the Low Grade (WHO G1/G2) Glioma (LGG) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
    Progression Free Survival (PFS) was 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 did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
12. Progression Free Survival (PFS) in the High Grade (WHO G3/G4) Glioma (HGG) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
    Progression Free Survival (PFS) was 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 did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
13. Progression Free Survival (PFS) in the Hairy Cell Leukemia (HCL) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
    Progression Free Survival (PFS) was 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 did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
14. Progression Free Survival (PFS) in the Multiple Myeloma (MM) Cohort [ 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 92 months (cut-off date for end of study = 10-Dec-21) ]
    Progression Free Survival (PFS) was 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 did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
15. Overall Survival (OS) in the Anaplastic Thyroid Cancer (ATC) Cohort [ Time Frame: From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
16. Overall Survival (OS) in the Biliary Tract Cancer (BTC) Cohort [ Time Frame: From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
17. Overall Survival (OS) in the Adenocarcinoma of the Small Intestine (ASI) Cohort [ Time Frame: From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
18. Overall Survival (OS) in the Low Grade (WHO G1/G2) Glioma (LGG) Cohort [ Time Frame: From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
19. Overall Survival (OS) in the High Grade (WHO G3/G4) Glioma (HGG) Cohort [ Time Frame: From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
20. Overall Survival (OS) in the Hairy Cell Leukemia (HCL) Cohort [ Time Frame: From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
21. Overall Survival (OS) in the Multiple Myeloma (MM) Cohort [ Time Frame: From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
22. Number of Participants With Adverse Events (AEs) [ Time Frame: From study treatment start date till 30 days safety follow-up, assessed up to 92 months (cut-off date for end of study = 10-Dec-21) ]
    The distribution of adverse events (AE) was 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.

Eligibility Criteria

• 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

Contacts and Locations

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, 4020

Novartis Investigative Site

Salzburg, Austria, 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

Copenhagen, Denmark, 2100

France

Novartis Investigative Site

Bordeaux Cedex, France, 33076

Novartis Investigative Site

Lyon Cedex 08, France, 69373

Novartis Investigative Site

Nantes cedex 1, France, 44093

Novartis Investigative Site

Saint-Herblain Cedex, France, 44805

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

Berlin, Germany, 13353

Novartis Investigative Site

Hamburg, Germany, 20246

Italy

Novartis Investigative Site

Milano, Lombardia, Italy, 20132

Novartis Investigative Site

Milano, Lombardia, Italy, 20133

Novartis Investigative Site

Milano, Lombardia, Italy, 20141

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, 03080

Novartis Investigative Site

Seoul, Korea, Republic of, 06273

Netherlands

Novartis Investigative Site

Amsterdam, Netherlands, 1066 CX

Novartis Investigative Site

Amsterdam, Netherlands, 1081 HV

Novartis Investigative Site

Rotterdam, Netherlands, 3015 GD

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

Sweden

Novartis Investigative Site

Stockholm, Sweden, 171 76

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] June 4, 2020

Statistical Analysis Plan  [PDF] January 10, 2022

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kreitman RJ, Moreau P, Ravandi F, Hutchings M, Gazzah A, Michallet AS, Wainberg ZA, Stein A, Dietrich S, de Jonge MJA, Willenbacher W, De Greve J, Arons E, Ilankumaran P, Burgess P, Gasal E, Subbiah V. Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. Blood. 2023 Mar 2;141(9):996-1006. doi: 10.1182/blood.2021013658.

Wen PY, Stein A, van den Bent M, De Greve J, Wick A, de Vos FYFL, von Bubnoff N, van Linde ME, Lai A, Prager GW, Campone M, Fasolo A, Lopez-Martin JA, Kim TM, Mason WP, Hofheinz RD, Blay JY, Cho DC, Gazzah A, Pouessel D, Yachnin J, Boran A, Burgess P, Ilankumaran P, Gasal E, Subbiah V. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. 2022 Jan;23(1):53-64. doi: 10.1016/S1470-2045(21)00578-7. Epub 2021 Nov 24.

Subbiah V, Lassen U, Elez E, Italiano A, Curigliano G, Javle M, de Braud F, Prager GW, Greil R, Stein A, Fasolo A, Schellens JHM, Wen PY, Viele K, Boran AD, Gasal E, Burgess P, Ilankumaran P, Wainberg ZA. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020 Sep;21(9):1234-1243. doi: 10.1016/S1470-2045(20)30321-1. Epub 2020 Aug 17.

Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, Wen PY, Zielinski C, Cabanillas ME, Urbanowitz G, Mookerjee B, Wang D, Rangwala F, Keam B. Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. J Clin Oncol. 2018 Jan 1;36(1):7-13. doi: 10.1200/JCO.2017.73.6785. Epub 2017 Oct 26.

Lee EQ, Ruland S, LeBoeuf NR, Wen PY, Santagata S. Successful Treatment of a Progressive BRAF V600E-Mutated Anaplastic Pleomorphic Xanthoastrocytoma With Vemurafenib Monotherapy. J Clin Oncol. 2016 Apr 1;34(10):e87-9. doi: 10.1200/JCO.2013.51.1766. Epub 2014 Aug 4. No abstract available.

• 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
• Results First Posted: August 21, 2023
• Last Update Posted: August 21, 2023
• Last Verified: July 2023

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 ):

solid tumors; anaplastic thyroid cancer (ATC); biliary tract cancer (BTC); gastrointestinal stromal tumor (GIST); low grade (WHO G1/G2) glioma (LGG); high grade (WHO G3/G4) glioma (HGG); non-seminomatous germ cell tumors (NSGCT)/non-germinomatous germ cell tumors (NGGCT); adenocarcinoma of the small intestine (ASI); hairy cell leukemia (HCL); multiple myeloma (MM); efficacy; safety; BRAF V600E mutation; Trametinib; Dabrafenib

Additional relevant MeSH terms:

Trametinib; Dabrafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action