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 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Differentiated Thyroid Cancer (DTC)
• Intervention / Treatment: Drug: Dabrafenib; Drug: Trametinib; Drug: Trametinib Placebo; Drug: Dabrafenib placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • CABA, Buenos Aires, Argentina, C1417DTB
      • Novartis Investigative Site
• Brazil
  • Rio de Janeiro
    • Rio de Janiero, Rio de Janeiro, Brazil, 20231-050
      • Novartis Investigative Site
  • Santa Catarina
    • Blumenau, Santa Catarina, Brazil, 89015-200
      • Novartis Investigative Site
  • São Paulo
    • São Paulo, São Paulo, Brazil, 01246-000
      • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Novartis Investigative Site
• China
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Guangzhou, China, 510060
    • Novartis Investigative Site
  • Shanghai, China, 200233
    • Novartis Investigative Site
  • Tianjin, China, 300052
    • Novartis Investigative Site
  • Tianjin, China, 300480
    • Novartis Investigative Site
  • Fujian
    • Fuzhou, Fujian, China, 350014
      • Novartis Investigative Site
  • Henan
    • Zhengzhou, Henan, China, 450008
      • Novartis Investigative Site
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410013
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210006
      • Novartis Investigative Site
    • Nanjing, Jiangsu, China, 210009
      • Novartis Investigative Site
    • Xuzhou, Jiangsu, China, 221003
      • Novartis Investigative Site
  • Jilin
    • Changchun, Jilin, China, 130033
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300121
      • Novartis Investigative Site
• India
  • Chennai, India, 600 020
    • Novartis Investigative Site
  • Haryana
    • Hisar, Haryana, India, 125005
      • Novartis Investigative Site
  • National Capital Territory of Delhi
    • New Delhi, National Capital Territory of Delhi, India, 110029
      • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
  • Pulau Pinang
    • George Town, Pulau Pinang, Malaysia, 10450
      • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03080
    • Novartis Investigative Site
  • Seoul, South Korea, 05505
    • Novartis Investigative Site
  • Seoul, South Korea, 06351
    • Novartis Investigative Site
  • Seoul, South Korea, 06591
    • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 704302
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• Turkey (Türkiye)
  • Fatih
    • Istanbul, Fatih, Turkey (Türkiye), 34098
      • Novartis Investigative Site
  • Merkez
    • Edirne, Merkez, Turkey (Türkiye), 22030
      • Novartis Investigative Site
  • Yenimahalle
    • Ankara, Yenimahalle, Turkey (Türkiye), 06500
      • Novartis Investigative Site
  • Yuregir
    • Adana, Yuregir, Turkey (Türkiye), 01250
      • Novartis Investigative Site
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Med School
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
• Vietnam
  • Hanoi, Vietnam, 100000
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• 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.

Key Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dabrafenib plus Trametinib; 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; Dabrafenib 150 mg capsule administered orally twice a day (BID); Other Names: DRB436; Drug: Trametinib; Trametinib 2 mg tablet administered once a day (QD); Other Names: TMT212
Placebo Comparator: Dabrafenib Placebo plus Trametinib Placebo; 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; matching placebo tablet for Trametinib 2 mg will be administered orally once a day (QD); Drug: Dabrafenib placebo; matching placebo capsule for Dabrafenib 150 mg will be administered orally twice a day (BID)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization to death assessed up to approximately 5 years
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.	From randomization assessed through Primary Analysis Cut-off date (approximately 3 years)
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.	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)	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.	Throughout study completion, an average 5 years
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).	Up to approximately 3 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2021
• Primary Completion (Actual): January 22, 2025
• Study Completion (Estimated): May 17, 2027

Study Registration Dates

• First Submitted: June 22, 2021
• First Submitted That Met QC Criteria: June 22, 2021
• First Posted (Actual): June 25, 2021

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Locally advanced or metastatic differentiated thyroid cancer; radio active iodine refractory; previously targeted therapy; BRAFV600E mutation; Differentiated Thyroid Cancer (DTC); B-Raf proto-oncogene, serine/threonine kinase (BRAF); Dabrafenib (DRB436); trametinib (TMT212)
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; dabrafenib; trametinib
• Other Study ID Numbers: CDRB436J12301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No