SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT01947023

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Phase 1 Study of Dabrafenib in Combination With Lapatinib in BRAF Mutant Thyroid Cancer

This phase I trial studies the side effects and best dose of lapatinib ditosylate when given together with dabrafenib in treating patients with thyroid cancer that cannot be removed by surgery and has not responded to previous treatment. Dabrafenib and lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01947023 BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Thyroid Gland Carcinoma Unresectable Thyroid Gland Carcinoma
MeSH: Carcinoma Thyroid Diseases Thyroid Neoplasms
HPO: Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

4 Interventions

Name: Dabrafenib

Description: Given PO

Type: Drug

Treatment (lapatinib ditosylate, dabrafenib)

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Treatment (lapatinib ditosylate, dabrafenib)

Name: Lapatinib Ditosylate

Description: Given PO

Type: Drug

Treatment (lapatinib ditosylate, dabrafenib)

Name: Pharmacological Study

Description: Correlative studies

Type: Other

Treatment (lapatinib ditosylate, dabrafenib)


Primary Outcomes

Description: MTD is defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity.

Measure: Maximum tolerated dose (MTD) of lapatinib ditosylate, in combination with the established dose of dabrafenib, defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity

Time: First 42 days of treatment

Secondary Outcomes

Description: Tissues such as phosphorylated mitogen-activated protein kinase 1 (ERK), human epidermal growth factor receptor (HER) 2, HER3, epidermal growth factor receptor (EGFR), platelet derived growth factor (PDGF), or protein kinase B (AKT) will be examined. Mean percent change will be calculated and compared.

Measure: Mean percent change in the post-treatment tissues relative to pre-treatment tissues for the phosphorylated protein targets examined

Time: Baseline to day 7 of course 1

Description: Genes including sodium/iodide symporter (NIS), dual-specificity phosphatase 5 (DUSP5), and plasminogen activator (PLAT) will be examined. Mean percentage change is calculated and compared with respect to each genotype.

Measure: Mean percentage change in transcript levels in the post-treatment tissues relative to pre-treatment tissues for several genes analyzed by reverse-transcriptase-polymerase chain reaction

Time: Baseline to day 7 of course 1

Purpose: Treatment

Single Group Assignment


There are 2 SNPs

SNPs


1 V600E

Mean percentage change is calculated and compared with respect to each genotype.. Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8 - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8 - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8 - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8 - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Thyroid Gland Carcinoma Unresectable Thyroid Gland Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of lapatinib (lapatinib ditosylate) that can be used in combination of dabrafenib. --- V600E ---


2 V600K

Mean percentage change is calculated and compared with respect to each genotype.. Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E --- --- V600K ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8 - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8 - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E --- --- V600K ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8 - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8 - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Thyroid Gland Carcinoma Unresectable Thyroid Gland Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of lapatinib (lapatinib ditosylate) that can be used in combination of dabrafenib. --- V600E --- --- V600K ---



HPO Nodes


HPO:
Abnormality of the thyroid gland
Genes 327
CDKN1A PCSK1 SOX3 CDKN1B GABRD TPO CDKN2B CDKN2C UBR1 IL12A TMEM67 IL12RB1 TREX1 PDE4D ZBTB20 PLVAP TRH STUB1 WDR4 SPIB TRHR MCM8 DNAJC19 MARS USP9X ENPP1 HLA-DRB1 PIEZO1 SLC26A4 ACP5 IQSEC2 GAS1 INSR MC2R GATA1 GATA6 CDH23 IRF5 RPS20 SRY TSC1 TSC2 GCH1 EXT2 TSHB TSHR KEAP1 EYA1 PTCH1 RREB1 PTEN BCOR ADA HNF4A ADAR TRIP13 GDNF ALX4 DDOST STAR HESX1 STAT1 PHF21A STAT3 TBC1D24 HIRA MEN1 NSDHL IFIH1 DACT1 BMP4 MALT1 SAA1 BMPR1A ARL6IP6 KISS1R SALL1 ALMS1 BRAF PROKR2 CLPB CLCNKB PIK3C2A PAX8 HPD PIK3CA FDX2 SGPL1 GLI2 GLI3 JAG1 KCNJ10 RNASEH2C SCN4A UFD1 BUB1 ARNT2 BUB1B VPS13A HRAS DCAF17 C1QBP MLH1 C1S ALG8 FGF8 AKT1 KIAA0556 BCL10 FGFR1 PLCG2 CDC73 GNAS SEMA4A HSD17B3 FOXH1 NODAL EIF2AK3 KDM6A TNFSF15 TRAPPC9 SEC23B TBX1 SDHB SDHC SDHD CDON FOXI1 GP1BB PMM2 TBX2 FOXP3 DUOXA2 FOXE1 PMS1 NPHS1 RNASEH2B KRAS CACNA1C RAG1 RAG2 FLII CACNA1S TCF4 SEMA3C HNF1B DMXL2 PMS2 FBLN5 ADAMTSL1 B3GLCT DEAF1 FMR1 NRAS LHX4 COMT SASH1 SLC25A4 GNE TCOF1 CLIP2 NRTN RNASEH2A WFS1 GPR35 NTRK1 RRM2B POLG EFEMP2 POLR1C WRN IYD KCNAB2 GLIS3 POMC APC SHH AIRE BAZ1B POU1F1 BIRC3 DUOX2 POU2AF1 CASP10 DNM1L CP TWNK NLRP1 CASR POU3F4 SAMHD1 MSH2 CHD7 MSH3 TDGF1 LHX3 AIP IDH1 MINPP1 IDH2 TXNRD2 RET RBM28 APOE RFC2 XRCC4 SIX1 SIX3 GTF2IRD1 ECE1 SKI DLL1 FAS FASLG TF EXOSC2 DICER1 JMJD1C ABCC6 LEP OPA1 LEPR MSTO1 EDN3 EDNRB POLR3A ZIC2 DNAH1 FAN1 TG SLC5A5 TTC7A MST1 RMRP TGFBR2 GPR161 LIFR POLR1D TGIF1 MSH6 RASGRP1 MLXIPL LIG4 SEMA3D LIMK1 KLLN KMT2D MLH3 OTX2 GTF2I MMEL1 THRA THRB SLC12A3 SEC24C LMNA COX1 COX2 COX3 IGH ARVCF WDR11 DCLRE1C SUGCT SLC16A2 NKX2-1 RCBTB1 CCBE1 FANCI BTNL2 PPP1R15B MRAP ND1 SETBP1 ND4 ND5 ND6 PTRH2 PRKAR1A LRP4 FLCN STEAP3 NKX2-5 ROBO1 PRKCD FOXP1 TRNF HABP2 TRNH FUCA1 ELN TRNL1 TRNL2 RERE CTNS GREM1 TRNN LRBA CTNNB1 KCNJ18 IGSF1 TRNQ TANGO2 TRNS1 TRNS2 BUB3 POLG2 FUT8 TRNW KAT6B HBB SUFU CEP57 IL2RA EPCAM PRDM16 IL2RG NNT TNPO3 TBL2 DISP1 RAI1 IL7R PROP1 SEMA3E GABRA3 NIN
Carcinoma
Genes 11
PTEN CDKN1B APC MLH1 MSH2 FGFR3 KIT DKC1 RSPO1 STK11 NLRP1
Neoplasm of the thyroid gland
Genes 61
FOXE1 CDKN1A PMS1 CDKN1B KRAS CDKN2B CDKN2C TGFBR2 MSH6 RASGRP1 SEMA3D SEMA3C BMPR1A PMS2 KLLN MLH3 NRAS LMNA NRTN PIK3CA NTRK1 SLC26A4 JAG1 KCNJ10 WRN HRAS APC MLH1 PRKAR1A FLCN CASP10 PRKCD AKT1 RPS20 HABP2 MSH2 MSH3 CDC73 KEAP1 GREM1 MINPP1 GNAS SEMA4A RET PTEN ECE1 FAS FASLG EPCAM GDNF DICER1 SEC23B EDN3 EDNRB SDHB SDHC SDHD FOXI1 MEN1 FAN1 TG
Thyroid adenoma
Genes 16
PTEN CDKN1A FAS CDKN1B FASLG PRKAR1A CDKN2B CDKN2C PIK3CA CASP10 PRKCD RASGRP1 AKT1 MSH3 CDC73 MEN1
Thyroid carcinoma
Genes 34
FOXE1 HRAS APC PRKAR1A FLCN CASP10 PRKCD RASGRP1 AKT1 BMPR1A HABP2 KLLN CDC73 KEAP1 GREM1 MINPP1 RET NRAS PTEN FAS FASLG PIK3CA DICER1 NTRK1 SEC23B SLC26A4 JAG1 KCNJ10 SDHB SDHC SDHD FOXI1 TG WRN
Thyroid follicular adenoma