Enhancing Radioiodine Incorporation Into BRAF Mutant Thyroid Cancers With the Combination of Vemurafenib and KTN3379

This is a patient pilot study testing the hypothesis that vemurafenib with the addition of
KTN3379 can restore iodine incorporation in BRAF mutant (MUT), radioiodine-refractory (RAIR)
thyroid cancer patients. Eligible patients with BRAF MUT, RAIR thyroid cancer will undergo
human recombinant TSH (rhTSH or Thyrogen)-stimulated 124I PET/CT lesional dosimetry to
quantify the baseline RAI avidity of index metastatic lesion(s). Patients will then receive
vemurafenib followed by the addition of KTN3379 after which a second Thyrogen-stimulated
124I PET/CT lesional dosimetry will be performed. For patients whose tumor(s) demonstrate
sufficient iodine incorporation warranting 131I therapy, Thyrogen-stimulated standard
dosimetry will be performed and therapeutic 131I will be administered concurrently with
vemurafenib and KTN3379. Subsequent to discontinuation of vemurafenib, tumor assessments
will be conducted with serial radiologic scan(s) and thyroglobulins (scans will be performed
at baseline, before 131I, 3 months (+/- 1 month) following 131I, and 6 months after 131I).

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed thyroid carcinoma of
follicular origin (including papillary, follicular, or poorly differentiated subtypes
and their respective variants).

- Confirmation in a CLIA certified laboratory or in an FDA-approved assay that one of
the patient's thyroid tumors (primary tumor, recurrent tumor, or metastasis)
possesses a BRAF mutation at V600.

- Patients must have measurable disease defined by RECIST criteria 1.1.

- Tumors in previously irradiated fields may be considered measureable if there is
evidence of tumor progression after radiation treatment.

- RAI-refractory disease on structural imaging

- Age ≥ 18 years.

- ECOG performance status ≤ 2

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count (ANC) > 1.5x109/L

- Hemoglobin ≥ 9 g/dL

- Platelets ≥ 100 x 109/L

- Albumin ≥ 2.5 g/dL

- Total bilirubin ≤ 1.5x institutional ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2x
institutional ULN unless it is related to the primary disease

- Creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
formula) ≥ 50 mL/min OR 24-hour urine creatinine clearance ≥ 50 mL/min

Exclusion Criteria:

- Concomitant malignancies or previous malignancies treated within the past 3 years.
Exception: Patients who have been disease-free for 3 years, patients with a history
of completely resected non-melanoma skin cancer, and/or patients with indolent
secondary malignancies, are eligible.

- Use of other investigational drugs within 28 days preceding the first dose of
vemurafenib on this study.

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression.

- History or evidence of cardiovascular risk including any of the following:

- Corrected QT (QTc) interval ≥ 450 msec at baseline or history of congenital long QT
syndrome or uncorrectable electrolyte abnormalities. (Patients with well controlled
atrial fibrillation are exempt from this criteria.)

- History of cerebrovascular attack or transient ischemic attack within 6 months prior
to the initiation of therapy on this protocol.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements.