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Differentiated Thyroid Cancer (DTC)Phase 3NCT04940052

Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Previously Treated Patients With Metastatic, Radio-active Iodine Refractory BRAF V600E Mutation Positive Differentiated Thyroid Cancer

A Phase 3 study testing Dabrafenib and Trametinib in people with Differentiated Thyroid Cancer (DTC), run by Novartis Pharmaceuticals at 41 sites in 11 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

The purpose of this study is to assess the efficacy and safety of dabrafenib in combination with trametinib for treating adult patients with locally advanced or metastatic Differentiated Thyroid Cancer (DTC) harboring the BRAFV600E mutation, who are refractory to radioactive iodine (RAI) therapy and have experienced… Read more about this study

Who is it for?
Ages 18 to 99 years
Conditions the study is for
Differentiated Thyroid Cancer (DTC)
What is being tested?
Dabrafenib and Trametinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
153 participants
Where
41 sitesin 11 countries
Study dates
15 Nov 2021to 25 May 2027
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Signed informed consent
  • Male or female ≥ 18 years of age at time of informed consent
  • Histologically or cytologically confirmed diagnosis of advanced/metastatic differentiated thyroid carcinoma
  • Radioactive-iodine refractory disease
  • BRAF V600E mutation-positive tumor sample as per central laboratory result
  • Has progressed on at least 1 but not more than 2 prior VEGFR targeted therapies
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • At least one measurable lesion as defined by RECIST v1.1.

Who cannot join

  • Anaplastic or medullary carcinoma of the thyroid
  • Previous treatment with a BRAF inhibitor and/or a MEK inhibitor
  • Concomitant RET Fusion-Positive Thyroid Cancer
  • Treatment with any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization
  • Treatment with any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before randomization
  • Treatment with 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 (RVO) or central serous retinopathy
  • Other inclusion/exclusion criteria may apply.

Trial locations and contacts

41 sites in 11 countries.

41 sites in 11 countries

China16 sites
  • Novartis Investigative Site

    Beijing, 100036

  • Novartis Investigative Site

    Beijing, 100730

  • Novartis Investigative Site

    Changchun, Jilin, 130033

  • Novartis Investigative Site

    Changsha, Hunan, 410013

  • Novartis Investigative Site

    Chengdu, Sichuan, 610041

  • Novartis Investigative Site

    Fuzhou, Fujian, 350014

  • Novartis Investigative Site

    Guangzhou, 510060

  • Novartis Investigative Site

    Nanjing, Jiangsu, 210006

  • Novartis Investigative Site

    Nanjing, Jiangsu, 210009

  • Novartis Investigative Site

    Shanghai, 200233

  • Novartis Investigative Site

    Tianjin, Tianjin Municipality, 300121

  • Novartis Investigative Site

    Tianjin, 300052

  • Novartis Investigative Site

    Tianjin, 300480

  • Novartis Investigative Site

    Wuhan, Hubei, 430022

  • Novartis Investigative Site

    Xuzhou, Jiangsu, 221003

  • Novartis Investigative Site

    Zhengzhou, Henan, 450008

Other trials in China

South Korea4 sites
  • Novartis Investigative Site

    Seoul, 03080

  • Novartis Investigative Site

    Seoul, 05505

  • Novartis Investigative Site

    Seoul, 06351

  • Novartis Investigative Site

    Seoul, 06591

Other trials in South Korea

Turkey (Türkiye)4 sites
  • Novartis Investigative Site

    Adana, Yuregir, 01250

  • Novartis Investigative Site

    Ankara, Yenimahalle, 06500

  • Novartis Investigative Site

    Edirne, Merkez, 22030

  • Novartis Investigative Site

    Istanbul, Fatih, 34098

Other trials in Turkey (Türkiye)

Brazil3 sites
  • Novartis Investigative Site

    Blumenau, Santa Catarina, 89015-200

  • Novartis Investigative Site

    Rio de Janiero, Rio de Janeiro, 20231-050

  • Novartis Investigative Site

    São Paulo, São Paulo, 01246-000

Other trials in Brazil

India3 sites
  • Novartis Investigative Site

    Chennai, 600020

  • Novartis Investigative Site

    Hisar, Haryana, 125005

  • Novartis Investigative Site

    New Delhi, National Capital Territory of Delhi, 110029

Other trials in India

Malaysia3 sites
  • Novartis Investigative Site

    George Town, Pulau Pinang, 10450

  • Novartis Investigative Site

    Kuala Lumpur, 59100

  • Novartis Investigative Site

    Kuching, Sarawak, 93586

Other trials in Malaysia

United States2 sites
  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Northwestern University Med School

    Chicago, Illinois, 60611

Other trials in United States

Canada2 sites
  • Novartis Investigative Site

    Edmonton, Alberta, T6G 1Z2

  • Novartis Investigative Site

    London, Ontario, N6A 5W9

Other trials in Canada

Taiwan2 sites
  • Novartis Investigative Site

    Tainan, 704302

  • Novartis Investigative Site

    Taipei, 10002

Other trials in Taiwan

Argentina1 site
  • Novartis Investigative Site

    CABA, Buenos Aires, C1417DTB

Other trials in Argentina

Vietnam1 site
  • Novartis Investigative Site

    Hanoi, 100000

Other trials in Vietnam

About this study

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)

The purpose of this study is to assess the efficacy and safety of dabrafenib in combination with trametinib for treating adult patients with locally advanced or metastatic Differentiated Thyroid Cancer (DTC) harboring the BRAFV600E mutation, who are refractory to radioactive iodine (RAI) therapy and have experienced disease progression following one or two prior VEGFR-targeted treatments.

Read the detailed description

This is a global, multicenter, randomized, double-blind, placebo-controlled Phase III study designed to evaluate the efficacy and safety of dabrafenib plus trametinib in adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that is positive for the BRAF V600E mutation, refractory to radioactive iodine (RAI), and has progressed following prior vascular endothelial growth factor receptor (VEGFR) targeted therapy.

After eligibility assessment, patients will be randomized in a 2:1 ratio to receive either dabrafenib plus trametinib or placebo. Patients will be stratified by the number of prior VEGFR targeted therapies (one versus two) and prior lenvatinib treatment (yes versus no).

The scientific objective guiding the primary estimand is based on progression-free survival (PFS) as per blinded independent review committee (BIRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

This study will enroll approximately 150 patients.

Patients randomized to the placebo arm who experience disease progression as per RECIST 1.1 confirmed by BIRC and meet eligibility criteria will have the option to cross over to the open-label combination of dabrafenib plus trametinib.

Treatment may continue beyond RECIST 1.1 disease progression (confirmed by BIRC) if, in the investigator's judgment, there is evidence of clinical benefit and the patient wishes to remain on study treatment. In cases where there is a discrepancy between local site determination and BIRC (for example, disease progression determined locally but not by BIRC), the patient should not be discontinued from study treatment until progression is confirmed by BIRC or, at a minimum, until one additional tumor assessment has been completed, provided this is clinically acceptable.

After treatment discontinuation, all patients will be followed for safety and efficacy evaluations during the post-treatment follow-up period. Subsequently, patient status will be collected every 12 weeks as part of survival follow-up.

This study is ongoing, and enrollment was completed on 09-May-2024. The primary analysis was performed after all patients had either completed at least 16 weeks of treatment or discontinued early, and after approximately 95 PFS events had occurred.

Being tested
Dabrafenib, Trametinib, Trametinib Placebo, Dabrafenib placebo
Keywords
Differentiated Thyroid Cancer (DTC), Locally advanced or metastatic differentiated thyroid cancer, radio active iodine refractory, previously targeted therapy, B-Raf proto-oncogene, serine/threonine kinase (BRAF), BRAFV600E mutation, Dabrafenib (DRB436), trametinib (TMT212)

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DabrafenibDrug

    Also called DRB436

    Dabrafenib 150 mg capsule administered orally twice a day (BID)

  • TrametinibDrug

    Also called TMT212

    Trametinib 2 mg tablet administered once a day (QD)

  • Trametinib PlaceboDrug

    matching placebo tablet for Trametinib 2 mg will be administered orally once a day (QD)

  • Dabrafenib placeboDrug

    matching placebo capsule for Dabrafenib 150 mg will be administered orally twice a day (BID)

Study groups in NCT04940052
Study groupRoleWhat they receive
Dabrafenib plus TrametinibExperimentalEligible participants will receive Dabrafenib 150 mg twice a day (BID) and Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.
Receives: Drug: Dabrafenib; Drug: Trametinib
Dabrafenib Placebo plus Trametinib PlaceboPlacebo comparatorEligible participants will receive matching placebo for Dabrafenib 150 mg twice a day (BID) and matching placebo for Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.
Receives: Drug: Trametinib Placebo; Drug: Dabrafenib placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival (PFS)

    Progression Free Survival (PFS) was defined as the time from the date of randomization to the date of the first documented progression according to RECIST 1.1 based on Blinded Independent Review Committee (BIRC) assessment, or death due to any cause.

    The primary analysis was conducted after all patients had either completed a minimum of 16 weeks of treatment or discontinued earlier, and following the occurrence of approximately 95 PFS events (Data cut-off date for the primary analysis was 22 January 2025).

    Measured: From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 3 years

Secondary outcomes (5)
  1. Overall Response Rate (ORR)

    Overall Response Rate (ORR) was defined as the proportion of participants who had a Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR) according to RECIST 1.1.

    Measured: From randomization assessed through Primary Analysis Cut-off date (approximately 3 years)

  2. Overall Survival (OS)

    Overall Survival (OS) is defined as the time from the date of randomization to the date of death due to any cause.

    Measured: From randomization to death assessed up to approximately 5 years

  3. Duration of Response (DOR)

    Duration of Response (DOR) applied only to patients whose Best Overall Response (BOR) was a confirmed Complete Response (CR) or Partial Response (PR) according to RECIST 1.1. The start date was defined as the date of the first documented confirmed CR or PR, and the end date corresponded to the date of the first documented confirmed progression or death from any cause. Patients who remained without progression or death from any cause were censored at the date of their last adequate tumor assessment prior to the initiation of any new antineoplastic therapy.

    Measured: From the first documented complete or partial response to the first documented progression or death, assessed up to Primary Analysis Cut-off date (approximately 3 years)

  4. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    The distribution of adverse events will be conducted through the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), based on the monitoring of relevant clinical and laboratory safety parameters. Treatment-emergent adverse events (TEAEs) in this study will be defined as events that begin after the first dose of study treatment and continue until 30 days after the last dose, or events that are present prior to the first dose and increase in severity based on preferred term within 30 days following the last dose.

    Measured: Throughout study completion, an average 5 years

  5. Number of Participants With Trametinib Associated Serous Retinopathy Ocular Events

    Analysis of the optical coherence tomography data was performed to assess the incidence, type, and severity of trametinib-associated serous retinopathy ocular events, using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grading system: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (death related to adverse event).

    Measured: Up to approximately 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Jun 2021
  2. Study start15 Nov 2021
  3. Primary completion22 Jan 2025
  4. Study completion25 May 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Model description
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 (1 versus 2) and prior Lenvatinib treatment (yes versus no).
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
153 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04940052
Sponsor's protocol ID
CDRB436J12301
Status last verified
Sep 2026
First submitted
22 Jun 2021
Last updated
21 Sep 2026
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • Gao M, Park YJ, Lin CC, Krzyzanowska MK, Li Z, Tsai HJ, Shi F, Qin J, Choong SH, Lin Y, Zhang Y, Kang JH, Hoff AO, Tan M, Roughton M, Paul M, Wirth LJ. Efficacy and safety of dabrafenib plus trametinib in adults with differentiated thyroid cancer: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2026 Aug;27(8):994-1003. doi: 10.1016/S1470-2045(26)00133-6. Epub 2026 Jul 13.

    PubMed 42442381

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Dabrafenib and Trametinib in people with Differentiated Thyroid Cancer (DTC), run by Novartis Pharmaceuticals at 41 sites in 11 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 41 sites in China, South Korea, Turkey (Türkiye), Brazil, India and 6 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 May 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression Free Survival (PFS) (time frame: From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04940052, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2026.

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