Differentiated Thyroid Cancer (DTC)
Conditions
Keywords
Differentiated Thyroid Cancer (DTC), Locally advanced or metastatic differentiated thyroid cancer, radio active iodine refractory, previously targeted therapy, B-Raf proto-oncogene, serine/threonine kinase (BRAF), BRAFV600E mutation, Dabrafenib (DRB436), trametinib (TMT212)
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 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.
Interventions
DRUGDabrafenib
Dabrafenib 150 mg capsule administered orally twice a day (BID)
DRUGTrametinib
Trametinib 2 mg tablet administered once a day (QD)
matching placebo tablet for Trametinib 2 mg will be administered orally once a day (QD)
DRUGDabrafenib placebo
matching placebo capsule for Dabrafenib 150 mg will be administered orally twice a day (BID)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
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 (1 versus 2) and prior Lenvatinib treatment (yes versus no).
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 3 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. 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | From randomization assessed through Primary Analysis Cut-off date (approximately 3 years) | 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. |
| 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 first documented complete or partial response to the first documented progression or death, assessed up to Primary Analysis Cut-off date (approximately 3 years) | 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. |
| 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 | Up to approximately 3 years | 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). |
Countries
Argentina, Brazil, Canada, China, India, Malaysia, South Korea, Taiwan, Turkey (Türkiye), United States, Vietnam
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
The study is conducted globally across 11 countries.
Pre-assignment details
Participants were randomized in a 2:1 ratio to either Dabrafenib plus Trametinib or placebo. Randomization was stratified by the number of prior VEGFR targeted therapies (1 vs. 2) and prior lenvatinib treatment (yes vs. no).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 10.15 |
| Prior lenvatinib treatment (yes vs no) No | 69 Participants |
| Prior lenvatinib treatment (yes vs no) Yes | 32 Participants |
| Prior Vascular Endothelial Growth Factor (VEGFR) targeted therapies (1 vs. 2) 1 | 79 Participants |
| Prior Vascular Endothelial Growth Factor (VEGFR) targeted therapies (1 vs. 2) 2 | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 131 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 17 / 101 | 3 / 52 | 7 / 30 | 10 / 84 | 16 / 49 | 6 / 23 |
| other Total, other adverse events | 96 / 101 | 44 / 52 | 30 / 30 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 43 / 101 | 13 / 52 | 14 / 30 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
None listed