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

Study Overview
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Brief Summary
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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)

Detailed Description
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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

Official Title
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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)

Conditions
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Differentiated Thyroid Cancer

Intervention / Treatment
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* Drug: Dabrafenib
* Drug: Trametinib
* Drug: Trametinib placebo
* Drug: Dabrafenib placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabrafenib plus trametinib<br>Participants will be treated with dabrafenib twice daily and trametinib once daily | Drug: Dabrafenib<br>* Dabrafenib will be administered orally twice daily<br>Drug: Trametinib<br>* Trametinib will be administered orally once daily<br>|
| Placebo Comparator: Placebo dabrafenib plus placebo trametinib<br>Participants will receive placebo dabrafenib twice daily and placebo trametinib once daily | Drug: Trametinib placebo<br>* Trametinib will be administered orally once daily<br>Drug: Dabrafenib placebo<br>* Dabrafenib placebo will be administered orally twice daily<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced or metastatic differentiated thyroid cancer, radio active iodine refractory, previously targeted therapy, BRAFV600E mutation, dabrafenib, trametinib