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

Papillary Thyroid Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01534897
• Other study ID #: 11-337
• Status: Completed
• Phase: N/A
• First received: February 10, 2012
• Last updated: June 16, 2015
• Start date: July 2012
• Est. completion date: March 2014

Study information

• Verified date: June 2015
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Days 21 and 22: The drug thyrogen will be administered as in injection into your buttocks on Days 21 and 22 in preparation for your whole body radioactive iodine scan on Day 28. Thyrogen is used as a diagnostic tool to help determine the status of your cancer and is approved for use in thyroid cancer patients.

Day 23: To prepare for the whole body radioactive iodine scan, you will be asked to swallow a capsule of radioactive iodine which will be absorbed by any remaining thyroid cells in your body. Radioactive iodine is approved for use in thyroid cancer patients. You will then be asked to return for the scan on Day 28.You will be asked to sign a separate consent for the radioactive iodine.

Days 1-28:

• Optional repeat fine needle aspirate Day 28

• Whole body radioactive iodine scan to assess your thyroid cancer

If your Day 28 whole body radioactive iodine scan demonstrates significant uptake of iodine, you will have the following tests done within 24 hours:

• Vital signs

• Routine blood tests (2 tablespoons)

• Research blood sample for CTCs. (4 teaspoons of blood)

• An injection of a therapeutic dose of radioactive iodine will be administered. If your Day 28 whole body radioactive iodine scan does not demonstrate significant uptake of iodine, you will be removed from the research study. You will have a 3 month follow up appointment as outlined below.

If your Day 28 whole body radioactive iodine scan demonstrates significant uptake of iodine, you will continue treatment with GSK2118436 and have the following study visits:

Days 35 and 36: The drug thyrogen will be administered as in injection into your buttocks on Days 35 and 36 in preparation for your whole body radioactive iodine scan on Day 42.

Day 37: You will be given a therapeutic dose of radioactive iodine. You will be given a separate consent form to sign for your radioactive iodine treatment. You will then be asked to return for the whole body radioactive iodine scan on Day 42.

Day 39:

• Vital signs

• Routine blood tests (1 tablespoon)

Day 42:

• Whole body radioactive iodine scan

• Research blood sample for CTCs. (4 teaspoons of blood)

After the final dose of the study drug: All participants will have a follow up visit 3 months after you stop the study drug. You will have the following tests at this visit:

• Routine blood tests (2 tablespoons)

• Research blood sample for CTCs. (4 teaspoons of blood)

• An assessment of your tumor by CT scan or PET/CT scan of your neck, chest, abdomen and pelvis.

• Those participants who had a therapeutic dose of radioactive iodine on Day 37 will have a whole body radioactive iodine scan.

• Optional fine needle aspirate

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Papillary Thyroid Carcinoma
• Thyroid Diseases
• Thyroid Neoplasms

Intervention

Drug:
• GSK2118436
150mg twice per day orally for 28 days (42 days if Iodine-131 scan on Day 25 shows new uptake)

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (1)

Rothenberg SM, McFadden DG, Palmer EL, Daniels GH, Wirth LJ. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res. 2015 Mar 1;21(5):1028-35. doi: 10.1158/1078-0432.CCR-14-2915. Epub — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Radioiodine Uptake	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).	2 years	No
Primary	Feasibility	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).	2 years	No
Secondary	Safety and Tolerability	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).	2 years	Yes
Secondary	Clinical Benefit	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.	2 years	No
Secondary	Pharmacodynamic Response	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.	2 years	No

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