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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02034110
• Collaborator: (none)
• Enrollment: 206
• Locations: 52
• Arm: 1
• Actual Duration (Months): 93
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 206 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: 9 indications9 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: Mar 12, 2014
• Actual Primary Completion Date: Dec 10, 2021
• Actual Study Completion Date: Dec 10, 2021

Arms and Interventions

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.; Other Names: DRB436 GSK2118436 ; Drug: Trametinib; Trametinib is 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) [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

1. Duration of Response (DoR) [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.

2. Progression Free Survival (PFS) based on Local Investigator assessment [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.

3. Overall Survival (OS) [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.

4. Incidence of Adverse events (AEs) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Little Rock	Arkansas	United States	72205
2	Novartis Investigative Site	Santa Monica	California	United States	90404
3	Novartis Investigative Site	Bethesda	Maryland	United States	20892
4	Novartis Investigative Site	Boston	Massachusetts	United States	02114
5	Novartis Investigative Site	Boston	Massachusetts	United States	02215
6	Novartis Investigative Site	New York	New York	United States	10016
7	Novartis Investigative Site	Nashville	Tennessee	United States	37203
8	Novartis Investigative Site	Houston	Texas	United States	77030
9	Novartis Investigative Site	Innsbruck		Austria	6020
10	Novartis Investigative Site	Linz		Austria	4010
11	Novartis Investigative Site	Salzburg		Austria	A-5020
12	Novartis Investigative Site	Wien		Austria	1090
13	Novartis Investigative Site	Jette		Belgium	1090
14	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
15	Novartis Investigative Site	Koebenhavn Oe		Denmark	2100
16	Novartis Investigative Site	Bordeaux Cedex		France	33076
17	Novartis Investigative Site	Caen Cedex 9		France	14 033
18	Novartis Investigative Site	Dijon Cedex		France	21079
19	Novartis Investigative Site	Lille Cedex		France	59020
20	Novartis Investigative Site	Lyon cedex 03		France	69437
21	Novartis Investigative Site	Nantes cedex 1		France	44093
22	Novartis Investigative Site	Saint-Herblain		France	44805
23	Novartis Investigative Site	Strasbourg Cedex		France	67091
24	Novartis Investigative Site	Toulouse Cedex 9		France	31059
25	Novartis Investigative Site	Villejuif Cedex		France	94805
26	Novartis Investigative Site	Freiburg	Baden-Wuerttemberg	Germany	79106
27	Novartis Investigative Site	Heidelberg	Baden-Wuerttemberg	Germany	69120
28	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg	Germany	68167
29	Novartis Investigative Site	Tuebingen	Baden-Wuerttemberg	Germany	72076
30	Novartis Investigative Site	Berlin		Germany	13353
31	Novartis Investigative Site	Hamburg		Germany	20246
32	Novartis Investigative Site	Roma	Lazio	Italy	00128
33	Novartis Investigative Site	Milano	Lombardia	Italy	20132
34	Novartis Investigative Site	Milano	Lombardia	Italy	20133
35	Novartis Investigative Site	Milano	Lombardia	Italy	20141
36	Novartis Investigative Site	Verona	Veneto	Italy	37134
37	Novartis Investigative Site	Chiba		Japan	277-8577
38	Novartis Investigative Site	Tokyo		Japan	104-0045
39	Novartis Investigative Site	Seoul		Korea, Republic of	06273
40	Novartis Investigative Site	Seoul		Korea, Republic of	110-744
41	Novartis Investigative Site	Seoul		Korea, Republic of	135-710
42	Novartis Investigative Site	Seoul		Korea, Republic of	138-736
43	Novartis Investigative Site	Amsterdam		Netherlands	1066 CX
44	Novartis Investigative Site	Amsterdam		Netherlands	1081 HV
45	Novartis Investigative Site	Nijmegen		Netherlands	6525 GA
46	Novartis Investigative Site	Rotterdam		Netherlands	3075 EA
47	Novartis Investigative Site	Utrecht		Netherlands	3584 CX
48	Novartis Investigative Site	Oslo		Norway	0310
49	Novartis Investigative Site	Barcelona		Spain	08035
50	Novartis Investigative Site	Madrid		Spain	28041
51	Novartis Investigative Site	Pamplona		Spain	31008
52	Novartis Investigative Site	Stockholm		Sweden	SE-171 76

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02034110
• Other Study ID Numbers: 117019; 2013-001705-87; CDRB436X2201; BRF117019
• First Posted: Jan 13, 2014
• Last Update Posted: Jun 10, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: solid tumors; efficacy; BRAF V600E mutation; trametinib; safety; Dabrafenib
• Additional relevant MeSH terms: Trametinib; Dabrafenib

Study Results

No Results Posted as of Jun 10, 2022