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Report for Clinical Trial NCT01534897

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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. 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.

NCT01534897 Papillary Thyroid Carcinoma
MeSH:Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

1 Interventions

Name: GSK2118436

Description: 150mg twice per day orally for 28 days (42 days if Iodine-131 scan on Day 25 shows new uptake)
Type: Drug
Group Labels: 1

GSK2118436


Primary Outcomes

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)

Secondary Outcomes

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 years

Description: 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 years

Description: 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 years

Description: 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 therapy

Purpose: Treatment

Allocation: N/A

Single Group Assignment


There is one SNP

SNPs


1 V600E

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 Neoplasms Thyroid Cancer, Papillary Thyroid Diseases 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 Neoplasms Thyroid Cancer, Papillary Thyroid Diseases You will take GSK2118436 capsules by mouth for 28 straight days. --- V600E --- --- V600E ---



HPO Nodes


HPO:
HP:0000820: Abnormality of the thyroid gland
Genes 475
SRD5A3 IYD IL2RG GABRA3 ATRX PAX8 IDH2 DMXL2 DUOX2 TNFSF15 GATA1 TCF4 KCNJ10 TWNK RRM2B TTC37 DCLRE1C MC2R ALX4 EXT2 PLCG2 SDHD XRCC4 GABRD FASLG TRNL1 BCL10 BUB1 NKX2-1 TSHR CHD7 FOXP3 FMR1 TSHB LHX4 SETBP1 PDE4D MST1 MALT1 MSTO1 SLC26A4 AIP CDH23 RPS20 GLIS3 BMPR1A SUFU TRNN GNAS TRNL2 PDE4D SUFU FOXP1 TBX1 PIEZO1 ND1 NRAS HBB CLCNKB COX2 EDN3 ZFAT EYA1 GCH1 EIF2AK3 EFEMP2 GLI2 TRAPPC9 PTEN PAX8 SEMA4A HABP2 UFD1 FGF8 PAX8 RNASEH2A LRBA TDGF1 B3GLCT FOXE1 LHX3 TG RET RMRP HRAS TSHR CTNS CASR NKX2-1 TRNQ HSD17B3 EDNRB CDKN2B JMJD1C SGPL1 NKX2-1 PROP1 IFNG THRB FLCN SLC5A5 THRB MLH1 POLG TSHR KCNJ18 KDM6A FUT8 CDKN1A CCBE1 IL12A LIG4 HLA-DRB1 FBLN5 TRNS1 ALMS1 DCLRE1C FOXE1 MSH3 TMEM67 CTNNB1 PAX8 TG POLG2 SEC24C SEMA3E SDHC ZIC2 TNPO3 SLC25A4 LEPR TSHR MMP2 USP9X FOXE1 LEP BIRC3 SDHB WDR4 GDNF LMNA CDKN1B LHX3 TRNL1 TBCK NNT THRA FOXI1 NNT COMT ACP5 POU1F1 SOX3 STAT1 PROKR2 GNAS VPS13A SEMA3D SOX3 TGFBR2 APC LIFR MINPP1 DISP1 CTNS THRB PROP1 SUGCT WDR11 DDOST COX1 TSHR ELN TBX1 PTEN LIG4 TXNRD2 ND5 SIX3 RAG1 ND4 TREX1 SEC23B TSHB CDKN1B RAI1 ADAT3 ELN TPO CEP57 USF3 FOXA2 RREB1 BUB3 SRY IGSF1 PDGFB CDC73 DUOXA2 DEAF1 BCOR FOXI1 PROP1 KLLN HSD17B3 KAT6B FOXP3 NSDHL DLL1 MMP14 WRN GP1BB GLI3 CEP57 BMP4 RFC2 NRTN SRGAP1 CACNA1S KISS1R PPP1R15B STAT3 ND6 CDKN2C TSHR TANGO2 HESX1 RET GPC1 STUB1 HNF1B AKT1 DICER1 TRNF NODAL SLC26A4 DNAJC19 PMM2 DICER1 CTLA4 PRDM16 ITCH GLI2 GNE SKI POLR1D KCNAB2 INSR SLC12A3 ENPP1 WFS1 GLI3 LIMK1 MRAP PTEN TBL2 RNASEH2B TWNK TGIF1 NKX2-5 ZBTB20 POMC TSHR PTEN YY1 DNM1L RERE NKX2-5 MARS1 SCN4A MSH3 ABCC6 IL7R GATA6 GREM1 PRKAR1A ADAMTSL1 POU3F4 EXOSC2 SLC6A17 LEPR KEAP1 CHD7 FUCA1 WFS1 APC IFIH1 HIRA RAI1 AFF4 PIK3C2A RBM28 FGFR1 ARNT2 KMT2D POU2AF1 SMARCB1 CLIP2 SEC23B CACNA1S ALG8 CP MEN1 TPO PPP1R15B PLVAP FAS SIX1 GNAS FANCI BUB1B RET DACT1 HABP2 C1QBP PTRH2 ADAR GAS1 ADA STAT1 SHH STAR IL12RB1 IRF5 FOXH1 TBC1D24 BMPR1A MINPP1 TRHR NKX2-5 POLR1C TRH DNAH1 PMS1 NKX2-1 PIK3CA RAG2 PCSK1 FDX2 GNAS FOXE1 MSTO1 RAI1 MSH6 TF TBX2 FLII FOXE1 TONSL APC STEAP3 BRAF PIK3CA SKIV2L TG HPD POLG LHX4 PROP1 PIK3CA EPCAM FOXD3 TRNS1 KCNJ18 MEN1 IQSEC2 SAA1 KRAS SLC5A5 KAT6B DUOX2 TRIP13 UBR1 SLC26A4 TSC2 IGH AKT1 USP9X ALMS1 PMS2 RCBTB1 APC HBB RASGRP1 CASP10 ROBO1 POU1F1 NPHS1 DMXL2 CDC73 ARVCF GTF2I DUOXA2 TRNW COX3 LHX4 POLR3A PLAA IL2RA CDON PRKAR1A HNF4A RNASEH2C JAG1 BTNL2 TRNH OPA1 DICER1 KIAA0556 NLRP1 TCOF1 APOE GPR35 TBX1 SLC16A2 PRKCD AIRE KCNJ10 HESX1 TRNS2 MLXIPL SAMHD1 TRMT10A LIG4 SEMA3C FMR1 CDH23 TANGO2 TSHR FLCN PTCH1 HESX1 BAZ1B FAN1 CDC73 POU1F1 GPR161 C1S IYD PHF21A MEN1 IDH1 LRP4 DUOX2 RET APC CACNA1C SASH1 PTEN TTC7A OTX2 MSH2 ECE1 APC TRNW MMEL1 SALL1 MCM8 XRCC4 DCAF17 FAS MLH3 SALL1 FOXP1 SPIB NF2 CLPB CDON LHX4 NIN ARL6IP6 GTF2IRD1 SLC26A4 TSC1 PRKAR1A
Protein Mutations 4
F11N K601E V600E V600K
SNP 0