Clinical trial NCT04940052: Study of Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer
Official title: A Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer (DTC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Differentiated Thyroid Cancer
Keywords: Locally advanced or metastatic differentiated thyroid cancer
radio active iodine refractory
previously targeted therapy
BRAFV600E mutation
dabrafenib
trametinib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-06-25
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 150 adults patients with locally advanced or metastatic BRAFV600E mutation-positive, differentiated thyroid carcinoma who are refractory to radioactive iodine and have progressed following prior VEGFR targeted therapy will enter in the trial. Patients will be randomized in a 2:1 ratio to either dabrafenib plus trametinib or placebo. Patients will be stratified by number of prior VEGFR targeted therapy (1versus2) and prior lenvatinib treatment (yes versus no)

Detailed description: This is a global, multicenter, randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety of dabrafenib plus trametinib in adult patients with locally advanced or metastatic BRAFV600E mutation-positive, differentiated thyroid cancer who are refractory to radioactive iodine and have progressed following prior VEGFR targeted therapy. After eligibility assessment, approximately 150 patients will be randomized in a 2:1 ratio to either dabrafenib plus trametinib or placebo. Patients will receive dabrafenib in combination with trametinib or placebo until disease progression as per RECIST 1.1 as determined by investigator and confirmed by BIRC or loss of clinical benefit as determined by investigator, death, unacceptable toxicity, pregnancy, withdrawal of consent, lost to follow-up or early termination of the study by the sponsor. Patients randomized in the placebo arm and for whom progression as per RECIST 1.1 is confirmed by blinded independent review committee and who meet the criteria will be given the option to cross over to the open label combination drug dabrafenib plus trametinib

Eligibility criteria: Inclusion Criteria:

* Signed informed consent must be obtained prior to performing any specific pre-screening and screening procedure
* Male or female \>= 18 years of age at the time of informed consent
* Histologically or cytologically confirmed diagnosis of advanced/metastatic differentiated thyroid cancer
* Radio active iodine refractory disease
* BRAFV600E mutation positive tumor sample as per Novartis designated central laboratory result
* Has progressed on at least 1 but not more than 2 prior VEGFR targeted therapy
* Eastern Cooperative Oncology Group performance status \>= 2
* At least one measurable lesion as defined by RECIST 1.1

Exclusion Criteria:

* Anaplastic or medullary carcinoma of the Tyroid
* Previous treatment with BRAF inhibitor and/or MEK inhibitor
* Concomitant RET Fusion Positive Thyroid cancer
* Receipt of any type of small molecule kinase inhibitor within 2 weeks before randomization
* Receipt of any type of cancer antibody or systemic chemotherapy within 4 weeks before randomization
* Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before randomization
* A history or current evidence/risk of retinal vein occlusion or central serous retinopathy

Primary outcomes:
measure: Progression Free Survival
timeFrame: From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 2 years
Secondary outcomes:
measure: Overall Response Rate
timeFrame: From randomization up to approximately 2 years
measure: Overall Survival
timeFrame: From randomization to death assessed up to approximately 5 years
measure: Duration of response
timeFrame: Duration of response from the start date of the first documented response of complete response or partial response and the date defined as the date of the first documented progression or death due to any cause up to 2 years
measure: Number of participants with trametinib associated serous retinopathy ocular events
timeFrame: screening, week 4, week 8, week 12, week 20 and every 12 weeks after week 20, up to approximately 2 years
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University Med School
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rio De Janiero
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Blumenau
country: Brazil
facility: Novartis Investigative Site
state: Santa Catarina
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Fuzhou
country: China
facility: Novartis Investigative Site
state: Fujian
city: Zhengzhou
country: China
facility: Novartis Investigative Site
state: Henan
city: Wuhan
country: China
facility: Novartis Investigative Site
state: Hubei
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Xuzhou
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Changchun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Tianjin
country: China
facility: Novartis Investigative Site
state: Tianjin
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Hisar
country: India
facility: Novartis Investigative Site
state: Haryana
city: Chennai
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kuching
country: Malaysia
facility: Novartis Investigative Site
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Pulau Pinang
country: Malaysia
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Edirne
country: Turkey
facility: Novartis Investigative Site
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
Study officials:
References: