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

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)

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)

Study Overview

• Status: Recruiting
• Conditions: Differentiated Thyroid Cancer
• 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 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

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1012AAR
    • Recruiting
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1417DTB
      • Recruiting
      • Novartis Investigative Site
• Brazil
  • Sao Paulo, Brazil, 01323-900
    • Recruiting
    • Novartis Investigative Site
  • RJ
    • Rio De Janiero, RJ, Brazil, 20231-050
      • Recruiting
      • Novartis Investigative Site
  • RS
    • Porto Alegre, RS, Brazil, 91350 200
      • Recruiting
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 01246-000
      • Recruiting
      • Novartis Investigative Site
  • Santa Catarina
    • Blumenau, Santa Catarina, Brazil, 89015-200
      • Recruiting
      • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Withdrawn
      • Novartis Investigative Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Recruiting
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Recruiting
      • Novartis Investigative Site
• China
  • Beijing, China, 100036
    • Recruiting
    • Novartis Investigative Site
  • Beijing, China, 100730
    • Recruiting
    • Novartis Investigative Site
  • Changsha, China, 410013
    • Recruiting
    • Novartis Investigative Site
  • Guangzhou, China, 510060
    • Recruiting
    • Novartis Investigative Site
  • Shanghai, China, 200233
    • Recruiting
    • Novartis Investigative Site
  • Tianjin, China, 300052
    • Recruiting
    • Novartis Investigative Site
  • Tianjin, China, 300480
    • Recruiting
    • Novartis Investigative Site
  • Fujian
    • Fuzhou, Fujian, China, 350013
      • Recruiting
      • Novartis Investigative Site
  • Henan
    • Zhengzhou, Henan, China, 450008
      • Recruiting
      • Novartis Investigative Site
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Recruiting
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210006
      • Recruiting
      • Novartis Investigative Site
    • Nanjing, Jiangsu, China, 210009
      • Recruiting
      • Novartis Investigative Site
    • Xuzhou, Jiangsu, China, 221003
      • Recruiting
      • Novartis Investigative Site
  • Jilin
    • Changchun, Jilin, China, 130033
      • Recruiting
      • Novartis Investigative Site
  • Shanxi
    • XI An, Shanxi, China, 710061
      • Recruiting
      • Novartis Investigative Site
    • Xi'an, Shanxi, China, 710032
      • Recruiting
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Recruiting
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300121
      • Recruiting
      • Novartis Investigative Site
  • Yunnan
    • Kunming City, Yunnan, China, 650000
      • Recruiting
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310014
      • Recruiting
      • Novartis Investigative Site
• India
  • Chennai, India, 600 020
    • Recruiting
    • Novartis Investigative Site
  • New Delhi, India, 110029
    • Recruiting
    • Novartis Investigative Site
  • Haryana
    • Hisar, Haryana, India, 125005
      • Recruiting
      • Novartis Investigative Site
  • Maharashtra
    • Mumbai, Maharashtra, India, 400056
      • Recruiting
      • Novartis Investigative Site
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632 004
      • Recruiting
      • Novartis Investigative Site
  • Telangana
    • Hyderabad, Telangana, India, 500082
      • Recruiting
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Recruiting
      • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Recruiting
    • Novartis Investigative Site
  • Pulau Pinang, Malaysia, 10990
    • Recruiting
    • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Recruiting
      • Novartis Investigative Site
  • Wilayah Persekutuan
    • Kuala Lumpur, Wilayah Persekutuan, Malaysia, 50586
      • Recruiting
      • Novartis Investigative Site
• Mexico
  • Chihuahua, Mexico, 31210
    • Recruiting
    • Novartis Investigative Site
  • Mexico CP
    • Ciudad de Mexico, Mexico CP, Mexico, 14080
      • Recruiting
      • Novartis Investigative Site
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Recruiting
      • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 70403
    • Recruiting
    • Novartis Investigative Site
  • Taipei, Taiwan, 10048
    • Recruiting
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01250
    • Recruiting
    • Novartis Investigative Site
  • Ankara, Turkey, 06100
    • Recruiting
    • Novartis Investigative Site
  • Ankara, Turkey, 06560
    • Recruiting
    • Novartis Investigative Site
  • Edirne, Turkey, 22030
    • Recruiting
    • Novartis Investigative Site
  • TUR
    • Istanbul, TUR, Turkey, 34098
      • Recruiting
      • Novartis Investigative Site
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University Med School
      • Principal Investigator: Jochen Lorch
      • Contact: Phone Number: 312-926-7358
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital Dept. of MGH (2)
      • Principal Investigator: Lori J. Wirth
      • Contact: Lara Wellis; Email: lwellis@mgh.harvard.edu
• Vietnam
  • Hanoi, Vietnam, 100000
    • Recruiting
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

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

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; Participants will be treated with dabrafenib twice daily and trametinib once daily	Drug: Dabrafenib; Dabrafenib will be administered orally twice daily; Drug: Trametinib; Trametinib will be administered orally once daily
Placebo Comparator: Placebo dabrafenib plus placebo trametinib; Participants will receive placebo dabrafenib twice daily and placebo trametinib once daily	Drug: Trametinib placebo; Trametinib will be administered orally once daily; Drug: Dabrafenib placebo; Dabrafenib placebo will be administered orally twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression Free Survival is based on the blinded independent review committee assessment using RECIST 1.1	From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	overall response rate is defined as the proportion of patients with best overall response of complete response or partial response assessed per blinded independent review committee using RECIST 1.1 criteria	From randomization up to approximately 2 years
Overall Survival	Overall survival is defined as the time from the date of randomization to the date of death to any cause.	From randomization to death assessed up to approximately 5 years
Duration of response	Duration of response only applies to patients whose best overall response is complete response or partial response according to RECIST 1.1 and based on blinded independent review committee.	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
Number of participants with trametinib associated serous retinopathy ocular events	Standard ophthalmic examination will by done by an ophthalmologist and optical coherence tomography conducted at mandated visit. Analysis using optical coherence tomography data will be done to assess the incidence, type and severity of ocular events	screening, week 4, week 8, week 12, week 20 and every 12 weeks after week 20, up to approximately 2 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2021
• Primary Completion (Estimated): July 19, 2024
• Study Completion (Estimated): August 16, 2024

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): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: trametinib; dabrafenib; Locally advanced or metastatic differentiated thyroid cancer; radio active iodine refractory; previously targeted therapy; BRAFV600E mutation
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• 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