Vemurafenib and Cobimetinib for the Treatment of Patients With High Risk Differentiated Thyroid Carcinoma With BRAFV600E Mutation

PRIMARY OBJECTIVE:

I. The proportion of BRAF mutated high-risk differentiated thyroid carcinoma patients who achieve excellent or indeterminate response with vemurafenib and cobimetinib treatment prior to initial radioactive iodine (RAI) therapy as defined by American Thyroid Association guideline.

SECONDARY OBJECTIVES:

I. The proportion of patients who had significant change on their I-123 scan before and after the targeted therapy.

II. To evaluate the safety and tolerability as determined by adverse events related to vemurafenib and cobimetinib combination therapy.

III. To evaluate the efficacy of vemurafenib and cobimetinib in enhancing RAI avidity by assessing the progression-free survival.

IV. To evaluate the diagnostic and prognostic value of thyroglobulin level as determined by thyroglobulin changes associated with treatment response.

V. To evaluate the tumor molecular characteristics in treatment responders as compared to non-responders.

OUTLINE:

Patients receive vemurafenib orally (PO) twice per day (BID) for 6 weeks and cobimetinib PO once per day (QD) for 3 weeks, followed by 1 week off, and then continuing for 2 weeks. Patients then receive iodine 131 PO followed by 3 additional days of vemurafenib PO BID and cobimetinib PO QD. Patients receive thyrogen intramuscularly (IM) daily for 2 days followed by I-123 diagnostic scan during screening and on study. Patients also undergo magnetic resonance imaging (MRI) during screening, positron emission tomography (PET) scan or computed tomography (CT) scan and blood sample collection throughout the study and ultrasound imaging and I-131 whole body scan during follow up.

After completion of study treatment, patients are followed up every 3 months for up to 12 months.

Primary Outcome Measures

1. Patients who achieve excellent or indeterminate response with vemurafenib and cobimetinib treatment prior to radioactive iodine therapy
   Excellent and indeterminate responses are defined by 2015 American Thyroid Association Management Guildelines for Differentiated Thyroid Cancer: * Excellent: Negative imaging and either suppresed thyroglobulin \< 0.2 ng/mL or TSH-stimulated thyroglobulin \< 1 ng/mL * Indeterminate: Nonspecific findings on imaging studies, faint uptake in thyroid bed on RAI scans, nonstimulated thyroglobulin detectable, but \<1 ng/mL, stimulated thyroglobulin detectable but \<10 ng/mL or thyroglobulin antibodies stable or declining in the absence of structural or functional disease

Secondary Outcome Measures

1. Proportion of patients who achieve increased iodine incorporation to a predicted lesion absorbed dose of 2000 cGy with I-131 dose of ≤ 300 mCi
2. Incidence of treatment related adverse events
   Will be summarized by type, severity (by Common Terminology Criteria for Adverse Events version 5.0 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution.
3. Progression free survival
   From initiation of study therapy to the first observation of disease relapse/progression or death from any cause, whichever occurs first.
4. Changes in thyroglobulin levels