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

Novartis

Status and phase: Active, not recruiting; Phase 3

Conditions: Differentiated Thyroid Cancer (DTC)

Treatments: Drug: Trametinib Placebo; Drug: Dabrafenib placebo; Drug: Dabrafenib; Drug: Trametinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04940052

CDRB436J12301

Details and patient eligibility

About

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.

Full 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.

Enrollment: 153 patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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/exclusion criteria may apply.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

---

153 participants in 2 patient groups, including a placebo group

Dabrafenib plus Trametinib

Experimental group

Description:

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.

Treatment:

Drug: Trametinib

Drug: Dabrafenib

Dabrafenib Placebo plus Trametinib Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Dabrafenib placebo

Drug: Trametinib Placebo