Clinical Trial: Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436

Brief Summary:

Radioactive iodine therapy is often part of the standard treatment for Papillary Thyroid Carcinoma (PTC) patients. However, in many patients, tumors develop a resistance or no longer respond to radioactive iodine therapy (iodine-refractory). Several lines of evidence suggest that blocking the BRAF gene may help to re-sensitize the tumors to radioactive iodine. BRAF is a protein that plays a central role in the growth and survival of cancer cells in some types of PTC. The investigational drug GSK2118436 may work by blocking the BRAF protein in cancer cells lines and tumors that have a mutated BRAF gene.

In this research study, the investigators are looking to see if GSK2118436 can re-sensitize iodine-refractory PTC to radioactive iodine therapy. The investigators are also looking at the safety of adding GSK2118436 to radioactive iodine therapy.

Detailed Summary:

You will take GSK2118436 capsules by mouth for 28 straight days. If your Day 28 whole body radioactive iodine scan demonstrates significant uptake of iodine, you will take GSK2118436 for an additional 14 days (Days 29-42). You will be given a drug diary to record when you take GSK2118436. This diary will also contain instructions on how to take GSK2118436.

Prior to Day 1

• Optional fine needle aspirate (pre-treatment) Day 1
• Vital signs
• Routine blood tests (2 tablespoons)
• Research blood sample for Circulating Tumor Cells (CTCs). (4 teaspoons of blood)
• Optional research blood sample for CTCs 4-6 hours after the first dose of GSK2118436

Day 2:

• Optional research blood sample for CTCs 4-6 hours after the first dose of GSK2118436 Day 3-5: Research blood sample for CTCs Days 8 and 15
• Vital signs
• Routine blood tests (2 tablespoons)
• Research blood sample for CTCs. (4 teaspoons of blood)
• Optional fine needle aspirate (Day 15 only) Low Iodine Diet: You will begin a low iodine diet on Day 15, in preparation for Day 23 when you will receive radioactive iodine (131I). The study team will provide you with instructions on this diet. The low iodine diet will be continued until the whole body scan is complete. For those participants who will receive a therapeutic dose of radioactive iodine on Day 37, the low iodine diet will be continued until the Day 42 whole body scan is complete.

Sponsor: Massachusetts General Hospital

Current Primary Outcome: Increased Radioiodine Uptake [ Time Frame: 25 days after start of Dabrafenib (GSK2118436) ]

Original Primary Outcome:

• Radioiodine Uptake [ Time Frame: 2 years ]
  To explore the hypothesis that treatment with GSK2118436 in patients with radioiodine-refractory metastatic BRAF V600E-mutant PTC will lead to increased radioiodine uptake in their disease sites (all patients).
• Feasibility [ Time Frame: 2 years ]
  To determine the feasibility, as defined by the ability to enroll and treat the specified number of patients, of: (a) administering GSK2118436 for 28 days in patients with BRAF V600E-mutant PTC, prior to whole body iodine scanning (all patients); and (b) administering GSK2118436 for an additional 14 days, prior to administering treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake after 28 days of treatment).

Current Secondary Outcome:

• Safety Analysis as Number of Participants With Adverse Events [ Time Frame: 2 years ]
  To evaluate the safety and tolerability, as determined by adverse event and serious adverse event reporting, of GSK2118436 in combination with whole body iodine scans (all patients) and treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake).
• Clinical Benefit as Measured by Change in Tumor Size [ Time Frame: 2 years ]
  To evaluate clinical benefit as measured by objective response rate per modified RECIST 1.1, which assesses changes in size of measurable tumors. (per RECIST, a partial response (PR) = at least 30% decrease in size of tumor; progressive disease (PD) = at least 20% increase in size of tumor; stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD).
• Number of Participants Who Complete the Study With Minimal Delays and no Dose Reductions [ Time Frame: 2 years ]
  To determine the feasibility of: (a) administering GSK2118436 for 28 days in patients with BRAF V600E-mutant PTC, prior to whole body iodine scanning (all patients); and (b) administering GSK2118436 for an additional 14 days, prior to administering treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake after 28 days of treatment).
• Clinical Benefit as Measured by Change in Thyroglobulin Level [ Time Frame: 3 months after radioiodine therapy ]
  To evaluate clinical benefit as measured by change in serum tumor marker, thyroglobulin. Rising thyroglobulin is generally indicative of tumor growth.

Original Secondary Outcome:

• Safety and Tolerability [ Time Frame: 2 years ]
  To evaluate the safety and tolerability, as determined by AE and SAE reporting, of GSK2118436 in combination with whole body iodine scans (all patients) and treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake).
• Clinical Benefit [ Time Frame: 2 years ]
  To evaluate parameters of clinical benefit as measured by decreases in the serum tumor marker, thyroglobulin, and objective response rate per modified RECIST 1.1.
• Pharmacodynamic Response [ Time Frame: 2 years ]
  To investigate the pharmacodynamic (PD) response to GSK2118436 as assessed in pre- and post-treatment circulating tumors cells (CTC—all patients) and fine needle aspirates (FNA) in consenting patients with accessible tumors by measuring: (i) phospho-ERK levels; (ii) sodium iodide symporter (NIS) levels; and (iii) the proliferation marker, Ki-67.

Dates:
Date Received: February 10, 2012
Date Started: July 2012
Date Completion:
Last Updated: January 24, 2017
Last Verified: January 2017