A Pilot Clinical Trial of Vemurafenib and Cobimetinib as a Redifferentiation Strategy in High-Risk, Radioactive Iodine (RAI) Naïve, BRAFV600E Mutated Differentiated Thyroid Carcinoma Patients Undergoing Initial RAI Therapy
This phase II trial tests how well vemurafenib and cobimetinib work in treating patients with high risk differentiated thyroid carcinoma with BRAFV600E mutation, in preparation for radioactive iodine therapy. Vemurafenib and cobimetinib are used in patients whose cancer has a mutated (changed) form of a gene called BRAF. They are in a class of medications called kinase inhibitors. They work by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving vemurafenib and cobimetinib may work better to treat patients with high risk differentiated thyroid carcinoma with BRAFV600E mutation, in preparation for radioactive iodine therapy.
• Documented informed consent of the participant and/or legally authorized representative
• Willingness to be followed for about 14 months
• Males or females aged ≥ 18 years at the time of informed consent
• Patients with thyroid carcinoma of follicular origin (papillary, follicular or Hurthle cell)
• Known positive BRAFV600E mutation (determined on a previous analysis and/or on a representative formalin-fixed paraffin embedded (FFPE) tumor samples or on a biopsy sample)
• High risk for recurrence according to the American Thyroid Association (ATA) guideline defined as having one or more of the features below:
‣ Gross extrathyroidal extension
⁃ FTC with extensive vascular invasion (\> 4), although less likely to have BRAF mutation
⁃ PTC with vascular invasion
⁃ Advanced nodal disease of (any node \>3 cm, \> 4 nodes, or extra-nodal extension)
⁃ BRAF+TERT promoter mutation
⁃ Post op thyroglobulin (TG) suggestive of distant metastasis
⁃ Distant metastatic sites (only for exploratory arm)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Blood pressure (BP) ≤ 140/90 mm Hg at screening with or without antihypertensive medications and no change in antihypertensive medications within 1 week prior to treatment start
• Creatinine clearance ≥ 50 mL/min according to the Cockcroft and Gault formula
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Hemoglobin ≥ 9.0 g/dL
• Platelet count ≥ 100 x 109/L
• Normal blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5
• Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome
• Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases)
• Women of childbearing potential must have a negative urine or serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment
• Agreement by women of childbearing potential (WOCBP) and males of childbearing potential\* to use an effective\*\* method of birth control\*\* for at least 3 months prior to screening through 1 year of study follow-up.
‣ Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)
∙ Effective birth control defined as hormonal and/or barrier contraception
• Non-English speaking persons and adults lacking capacity to consent are not excluded from participation