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

This study has been completed.
Information provided by (Responsible Party):
Stephen Rothenberg, M.D., Massachusetts General Hospital Identifier:
First received: February 10, 2012
Last updated: June 16, 2015
Last verified: June 2015

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.

Condition Intervention
Papillary Thyroid Carcinoma
Drug: GSK2118436

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436

Resource links provided by NLM:

Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Radioiodine Uptake [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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).

Secondary Outcome Measures:
  • Safety and Tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.

Enrollment: 11
Study Start Date: July 2012
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2118436
Intervention: GSK2118436 (dabrafenib) 150mg by mouth twice per day for 28 days, continued to day 42 if the Day 25 Iodine-131 scan shows new uptake. Patients with new Iodine-131 uptake on Day 25 who continue dabrafenib to day 42 receive a treatment dose (150 mCi) of Iodine-131 on Day 37.
Drug: GSK2118436
150mg twice per day orally for 28 days (42 days if Iodine-131 scan on Day 25 shows new uptake)
Other Name: Dabrafenib

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Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
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Please refer to this study by its identifier: NCT01534897

United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Massachusetts General Hospital
Principal Investigator: Stephen M Rothenberg, MD, PhD Massachusetts General Hospital
  More Information

Additional Information:
Responsible Party: Stephen Rothenberg, M.D., Prinicpal Investigator, Massachusetts General Hospital Identifier: NCT01534897     History of Changes
Other Study ID Numbers: 11-337
Study First Received: February 10, 2012
Last Updated: June 16, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Massachusetts General Hospital:
thyroid cancer
Tall cell PTC
Poorly differentiated thyroid carcinoma

Additional relevant MeSH terms:
Thyroid Diseases
Thyroid Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Head and Neck Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses processed this record on November 30, 2015