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

Differentiated Thyroid Cancer Clinical Trial

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04940052
• Other study ID #: CDRB436J12301
• Status: Recruiting
• Phase: Phase 3
• Start date: November 15, 2021
• Est. completion date: June 23, 2027

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: June 23, 2027
• Est. primary completion date: May 26, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Differentiated Thyroid Cancer
• Thyroid Diseases
• Thyroid Neoplasms

Intervention

Drug:
• Dabrafenib
Dabrafenib will be administered orally twice daily
• Trametinib
Trametinib will be administered orally once daily
• Trametinib placebo
Trametinib will be administered orally once daily
• Dabrafenib placebo
Dabrafenib placebo will be administered orally twice daily

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Brazil	Novartis Investigative Site	Blumenau	Santa Catarina
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio De Janiero	RJ
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Changchun	Jilin
China	Novartis Investigative Site	Changsha
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Fuzhou	Fujian
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Kunming City	Yunnan
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Tianjin
China	Novartis Investigative Site	Tianjin
China	Novartis Investigative Site	Tianjin	Tianjin
China	Novartis Investigative Site	Wuhan	Hubei
China	Novartis Investigative Site	XI An	Shanxi
China	Novartis Investigative Site	Xi'an	Shanxi
China	Novartis Investigative Site	Xuzhou	Jiangsu
China	Novartis Investigative Site	Zhengzhou	Henan
India	Novartis Investigative Site	Chennai
India	Novartis Investigative Site	Hisar	Haryana
India	Novartis Investigative Site	Hyderabad	Telangana
India	Novartis Investigative Site	Mumbai	Maharashtra
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Vellore	Tamil Nadu
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Malaysia	Novartis Investigative Site	Kuala Lumpur	Wilayah Persekutuan
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuching	Sarawak
Malaysia	Novartis Investigative Site	Pulau Pinang
Mexico	Novartis Investigative Site	Chihuahua
Mexico	Novartis Investigative Site	Ciudad de Mexico	Mexico CP
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
Taiwan	Novartis Investigative Site	Tainan
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Edirne
Turkey	Novartis Investigative Site	Istanbul	TUR
United States	Massachusetts General Hospital Dept of MGH 2	Boston	Massachusetts
United States	Northwestern University Med School	Chicago	Illinois
Vietnam	Novartis Investigative Site	Hanoi

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Vietnam,  Argentina,  Brazil,  Canada,  China,  India,  Korea, Republic of,  Malaysia,  Mexico,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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