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
- Conditions
- Differentiated Thyroid Cancer (DTC)
- Interventions
- Registration Number
- NCT04940052
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
- 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 carcinoma who are refractory to radioactive iodine and have progressed following prior VEGFR targeted therapy. The scientific objective guiding the primary estimand is based on the Progression Free Survival (PFS) as per BIRC assessment using RECIST 1.1 criteria.
Patients randomized in the placebo arm for whom disease progression as per RECIST 1.1 is confirmed by Blinded Independent Review Committee (BIRC) and who meet the eligibility criteria outlined in the study protocol will be given the option to crossover to the open-label dabrafenib plus trametinib treatment.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 153
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Dabrafenib plus Trametinib Dabrafenib 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. Dabrafenib plus Trametinib 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. Dabrafenib Placebo plus Trametinib Placebo 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. Dabrafenib Placebo plus Trametinib Placebo Dabrafenib 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.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 2 years 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.
- Secondary Outcome Measures
Name Time Method Overall Response Rate (ORR) From randomization up to approximately 2 years Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR), as per Blinded Independent Review Committee (BIRC) assessment and according to RECIST 1.1.
Overall Survival (OS) From randomization to death assessed up to approximately 5 years Overall Survival (OS) is defined as the time from the date of randomization to the date of death due to any cause.
Duration of Response (DOR) 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 Duration of Response (DOR) applied only to patients whose Best Overall Response (BOR) was a confirmed Complete Response (CR) or Partial Response (PR), as determined by the Blinded Independent Review Committee (BIRC) assessment 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.
Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) Throughout study completion, an average 5 years 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.
Number of participants with trametinib associated serous retinopathy ocular events screening, week 4, week 8, week 12, week 20 and every 12 weeks after week 20, up to approximately 2 years Standard ophthalmic examinations were performed by an ophthalmologist, and Optical Coherence Tomography (OCT) was conducted at mandated visits. Analysis of the optical coherence tomography data was carried out to evaluate the incidence, type, and severity of ocular events.
Trial Locations
- Locations (3)
Northwestern University Med School
🇺🇸Chicago, Illinois, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Novartis Investigative Site
🇻🇳Hanoi, Vietnam
Northwestern University Med School🇺🇸Chicago, Illinois, United States