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.
Name: GSK2118436
Description: 150mg twice per day orally for 28 days (42 days if Iodine-131 scan on Day 25 shows new uptake)Type: DrugGSK2118436
Description: Number of patients with radioiodine-refractory metastatic BRAF V600E-mutant PTC who have increased radioiodine uptake in their disease sites while on dabrafenib. Radioiodine uptake is assessed by whole body scan and areas of interest are identified by nuclear medicine physicians.
Measure: Increased Radioiodine Uptake Time: 25 days after start of Dabrafenib (GSK2118436)Description: 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).
Measure: Safety Analysis as Number of Participants With Adverse Events Time: 2 yearsDescription: 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).
Measure: Clinical Benefit as Measured by Change in Tumor Size Time: 2 yearsDescription: 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).
Measure: Number of Participants Who Complete the Study With Minimal Delays and no Dose Reductions Time: 2 yearsDescription: To evaluate clinical benefit as measured by change in serum tumor marker, thyroglobulin. Rising thyroglobulin is generally indicative of tumor growth.
Measure: Clinical Benefit as Measured by Change in Thyroglobulin Level Time: 3 months after radioiodine therapySingle Group Assignment
There is one SNP
Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436. --- V600E ---
Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436 Radioactive iodine therapy is often part of the standard treatment for Papillary Thyroid Carcinoma (PTC) patients. --- V600E ---
Number of patients with radioiodine-refractory metastatic BRAF V600E-mutant PTC who have increased radioiodine uptake in their disease sites while on dabrafenib. --- V600E ---
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. --- V600E ---
Rising thyroglobulin is generally indicative of tumor growth.. Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Papillary Thyroid Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary You will take GSK2118436 capsules by mouth for 28 straight days. --- V600E ---
Rising thyroglobulin is generally indicative of tumor growth.. Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Papillary Thyroid Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary You will take GSK2118436 capsules by mouth for 28 straight days. --- V600E --- --- V600E ---