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

NCT04940052 | Active Not Recruiting Phase 3 Results FDA Drug

• 1 other identifier: CDRB436J12301
• Study Type: interventional
• Target: 153
• Locations: 11 countries
• Sites: 41

Brief 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 disease progression following one or two prior VEGFR-targeted treatments.

Conditions

Differentiated Thyroid Cancer (DTC)

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)

Outcome Measures

Primary Outcomes (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).

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

Secondary Outcomes (5)

• Overall Response Rate (ORR)

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

• Overall Survival (OS)

  From randomization to death assessed up to approximately 5 years

• Duration of Response (DOR)

  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)

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

  Throughout study completion, an average 5 years

• Number of Participants With Trametinib Associated Serous Retinopathy Ocular Events

  Up to approximately 3 years

Study Arms (2)

Dabrafenib plus Trametinib

EXPERIMENTAL

Eligible 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.

Drug: Dabrafenib; Drug: Trametinib

Dabrafenib Placebo plus Trametinib Placebo

PLACEBO COMPARATOR

Eligible 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.

Drug: Trametinib Placebo; Drug: Dabrafenib placebo

Interventions

Dabrafenib DRUG

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

Also known as: DRB436

Dabrafenib plus Trametinib

Trametinib DRUG

Trametinib 2 mg tablet administered once a day (QD)

Also known as: TMT212

Dabrafenib plus Trametinib

Trametinib Placebo DRUG

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

Dabrafenib Placebo plus Trametinib Placebo

Dabrafenib placebo DRUG

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

Dabrafenib Placebo plus Trametinib Placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (41)

Northwestern University Med School

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

CABA, Buenos Aires, C1417DTB, Argentina

Location

Novartis Investigative Site

Rio de Janiero, Rio de Janeiro, 20231-050, Brazil

Location

Novartis Investigative Site

Blumenau, Santa Catarina, 89015-200, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 01246-000, Brazil

Location

Novartis Investigative Site

Edmonton, Alberta, T6G 1Z2, Canada

Location

Novartis Investigative Site

London, Ontario, N6A 5W9, Canada

Location

Novartis Investigative Site

Fuzhou, Fujian, 350014, China

Location

Novartis Investigative Site

Zhengzhou, Henan, 450008, China

Location

Novartis Investigative Site

Wuhan, Hubei, 430022, China

Location

Novartis Investigative Site

Changsha, Hunan, 410013, China

Location

Novartis Investigative Site

Nanjing, Jiangsu, 210006, China

Location

Novartis Investigative Site

Nanjing, Jiangsu, 210009, China

Location

Novartis Investigative Site

Xuzhou, Jiangsu, 221003, China

Location

Novartis Investigative Site

Changchun, Jilin, 130033, China

Location

Novartis Investigative Site

Chengdu, Sichuan, 610041, China

Location

Novartis Investigative Site

Tianjin, Tianjin Municipality, 300121, China

Location

Novartis Investigative Site

Beijing, 100036, China

Location

Novartis Investigative Site

Beijing, 100730, China

Location

Novartis Investigative Site

Guangzhou, 510060, China

Location

Novartis Investigative Site

Shanghai, 200233, China

Location

Novartis Investigative Site

Tianjin, 300052, China

Location

Novartis Investigative Site

Tianjin, 300480, China

Location

Novartis Investigative Site

Hisar, Haryana, 125005, India

Location

Novartis Investigative Site

New Delhi, National Capital Territory of Delhi, 110029, India

Location

Novartis Investigative Site

Chennai, 600 020, India

Location

Novartis Investigative Site

George Town, Pulau Pinang, 10450, Malaysia

Location

Novartis Investigative Site

Kuching, Sarawak, 93586, Malaysia

Location

Novartis Investigative Site

Kuala Lumpur, 59100, Malaysia

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Seoul, 05505, South Korea

Location

Novartis Investigative Site

Seoul, 06351, South Korea

Location

Novartis Investigative Site

Seoul, 06591, South Korea

Location

Novartis Investigative Site

Tainan, 704302, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Istanbul, Fatih, 34098, Turkey (Türkiye)

Location

Novartis Investigative Site

Edirne, Merkez, 22030, Turkey (Türkiye)

Location

Novartis Investigative Site

Ankara, Yenimahalle, 06500, Turkey (Türkiye)

Location

Novartis Investigative Site

Adana, Yuregir, 01250, Turkey (Türkiye)

Location

Novartis Investigative Site

Hanoi, 100000, Vietnam

Location

MeSH Terms

Interventions

dabrafenib; trametinib

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: June 22, 2021
• First Posted: June 25, 2021
• Study Start: November 15, 2021
• Primary Completion: January 22, 2025
• Study Completion (Estimated): May 25, 2027
• Last Updated: June 26, 2026
• Results First Posted: May 22, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share

Locations

AR (1); MY (3); US (2); CN (16); BR (3); KR (4); TW (2); TU (4); VN (1); CA (2); IN (3)