This study is NOT currently recruiting participants.
Number
14-C-0131
Sponsoring Institute
National Cancer Institute (NCI)
Recruitment Detail
Type: Completed Study; data analyses ongoing Gender: Male & Female Min Age: 18 Years Max Age: N/A
Referral Letter Required
No
Population Exclusion(s)
Fetuses;Adults who are or may become unable to consent;Pregnant Women;Children
Keywords
Hairy Cell Leukemia; Combination Therapy; Anaplastic Thyroid Cancer
Recruitment Keyword(s)
None
Condition(s)
Anaplastic Thyroid Cancer; Hairy Cell Leukemia
Investigational Drug(s)
Dabrafenib Trametinib
Investigational Device(s)
Intervention(s)
Drug: Dabrafenib Drug: Trametinib
Supporting Site
National Cancer Institute
- MEK is a human protein that helps regulate the growth of normal cells and many human cancers. It can be activated by mutations in specific proteins, including BRAF. The BRAF V600E mutation can cause tumors. Two drugs, dabrafenib and trametinib, inhibit BRAF and MEK. Researchers want to know if taking these drugs is effective and safe for treating cancers with BRAF V600E. This study will include two of nine rare cancers: Anaplastic Thyroid Cancer (ATC) and Hairy Cell Leukemia (HCL).
Objective:
- To see if a drug combination is effective and safe for treating cancers with the BRAF V600E mutation.
Eligibility:
- Adults 18 and older with ATC or HCL that has the BRAF V600E mutation.
Design:
- Participants will be screened with medical history, physical exam, and blood and urine tests. A sample of their tumor will be tested. They will have tests of their skin, eyes, and heart. They will have scans of their bodies. They will lie in a machine that takes pictures of their body.
- Day 1: Participants will get the study drugs to take at home. One is taken once daily, the other twice daily.
- Participants will have a physical exam and blood, tumor, and heart tests.
- Day 15: Participants will have tests of their blood and tumor samples.
- Participants will visit the clinic monthly to repeat many of the screening tests and get study drugs.
- At the end of the study, participants will repeat many of the screening tests. They will have monthly follow-up skin tests for about 6 months. They will be contacted by phone every 3 months.
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INCLUSION CRITERIA: -Signed, written informed consent -Sex: male or female -Age:greater than or equal to18 years of age at the time of providing informed consent. -Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2. -Must have advanced disease and no standard treatment options as determined by locally/regionally available standards of care and treating physician s discretion. -Must have a BRAF V600E mutation-positive tumor as confirmed by an approved local laboratory or sponsor designated central reference laboratory. -NOTE: All subjects must provide an archived or fresh tumor sample (for solid tumors) or a fresh BM aspirate and peripheral blood sample (for HCL and MM) for confirmation testing of the BRAF V600E mutation by a sponsor designated central reference laboratory using the a sponsor designated assay. -ATC, BTC, GIST, NSGCT/NGGCT, and ASI ONLY: Must have at least one measurable lesion per RECIST 1.1 outside of a prior radiation field or within the field with evidence of progression. -Able to swallow and retain orally administered medication. -Female Subjects of Childbearing Potential: Subjects must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agrees to use highly effective contraception, as defined in Section 9.1, from 7 days prior to enrollment, throughout the treatment period and for 16 weeks following discontinuation of trametinib when taken in combination with dabrafenib, or for 2 weeks following discontinuation of dabrafenib monotherapy. -Has adequate baseline organ function -French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. Histology Specific Inclusion Criteria: ATC 1. Histologically or cytologically confirmed, unresectable, metastatic ATC including ATC originating from within well-differentiated thyroid cancers or an ATC as part of a thyroid carcinoma of another histologic type. NOTE: Squamoid differentiated subtype is not permitted. Diagnosis noted to be consistent with ATC with presence of thyroid mass is acceptable. 2. Has undergone evaluation via indirect or direct laryngoscopy to ensure patency of trachea/airway prior to enrollment if bulky thyroid/neck masses are present and/or airway obstruction is suspected. 3. Has undergone prior external beam radiotherapy and/or surgery to the primary tumor. NOTE: Subjects with small primary tumor that has been totally removed by surgical excision whereby no radiotherapy was indicated (only metastatic lesions are manifested) or subjects with metastatic disease who do not require radiation or surgery to the neck mass will be eligible for participation in the study. BTC 1. Histologically or cytologically confirmed, unresectable, metastatic or locally advanced or recurrent adenocarcinoma of the biliary tract or gallbladder 2. Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to treatment with a gemcitabine-based chemotherapy regimen. GIST 1. Histologically confirmed diagnosis of c-Kit and PDGFRA wild-type GIST. 2. Must have metastatic or locally advanced, unresectable, or recurrent post-surgical disease. 3. Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to treatment with a TKI ( i.e., imatinib,sunitinib). WHO Grade 1 and 2 Glioma 1. Histologically confirmed recurrent or progressive WHO Grade 1 or 2 glioma 2. For WHO Grade 1 glioma ONLY: To be considered eligible for study treatment, subject must: a. Present with adequate level of favorable risk/benefit ratio including, but not limited to, the exhibited initial symptoms, AND b. Be evaluated by a panel of neuro-oncologists and the Medical Lead prior to enrollment. 3. For WHO Grade 2 glioma ONLY: To be considered eligible for study treatment, subject must not be eligible for treatment with chemotherapy. 4. Must have measurable non-enhancing disease based on two-dimensional magnetic resonance imaging (MRI) with contrast assessments as per RANO response criteria, NOTE: Enhancing disease is acceptable for pilocytic astrocytomas. 5.Must be receiving a stable or decreasing dose of corticosteroid treatment for 7 days prior to first dose of study treatment. NOTE: Steroids dose is limited to up to 8 mg/day of dexamethasone or equivalent dose of steroid. NOTE: Subjects are not required to be on corticosteroids to be eligible. WHO Grade 3 or 4 Glioma 1. Histologically confirmed recurrent or progressive WHO Grade 3 or 4 glioma. 2. Had prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiation therapy. NOTE: Subjects who have a WHO Grade 3 or 4 glioma for which chemotherapy and/or radiotherapy is not considered standard of care may remain eligible for the study. Consult the Medical Lead to discuss and determine if subject is eligible for enrollment. 3. Must have measurable disease at least 1 cm x 1 cm as per RANO response criteria 4. Must be receiving a stable or decreasing dose of corticosteroid treatment for 7 days prior to first dose of study treatments. NOTE: Steroids dose is limited to up to 8 mg/day of dexamethasone or equivalent dose of steroid. NOTE; Subjects are not required to be on corticosteroids to be eligible. NSGCT/NGGCT 1. Histologically confirmed NSGCT/NGGCT. 2. Must have either: -Refractory disease defined as disease progression during or relapsed after salvage high-dose chemotherapy (HDCT), or disease progression during cisplatin-based salvage chemotherapy. OR -Relapsed disease and ineligible for cisplatin-based salvage chemotherapy or HDCT. ASI 1. Histologically confirmed, metastatic or locally advanced ASI, adenocarcinoma of the ampulla, or adenocarcinoma of the peri-ampulla. 2. Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to one line of chemotherapy. HCL 1. Histologically confirmed diagnosis of HCL according to morphological and immunophenotypic criteria of WHO classification (WHO-2008) of lymphoid neoplasms. 2. Must have either: - Refractory disease defined as no response or disease progression in less than or equal to 1 year following first-line treatment with a purine analog (i.e., pentostatin, cladribine or fludarabine) OR - Relapsed disease defined as having relapsed following treatment with at least two prior treatments 3. Must have the presence of leukemic cells in the peripheral blood or BM aspirate or BM biopsy AND one or more of the following: - Bulky/symptomatic splenomegaly - Hemoglobin <10 g/dL - Platelets <100 times 10(9)/L - Absolute neutrophil count (ANC) <1 times 10(9)/L 4. For subjects with an opportunistic infection: the infection: the infection must be adequately managed and the subject must be clinically stable. The investigator may discuss this issue with the Medical Lead. MM 1. Histologically confirmed secretory MM. 2. Has received at least 2 prior lines of therapy, such as prior treatment with a proteasome inhibitor and IMiD, and is now refractory or has demonstrated intolerance (despite standard measures of supportive care and dose reduction) to the most recent therapy received 3. Must have measurable disease of MM as defined by at least ONE of the following: - Serum M-protein greater than or equal to 1 g/dL (greater than or equal to10 g/L) - Urine M-protein greater than or equal to 200 mg/24 hr - Serum free light chain (FLC) assay: involved FLC level greater than or equal to 5 mg/dL (greater than or equal to 50 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65), or - Biopsy proven plasmacytoma (measured within 28 days of Screening) 4. For subjects with an opportunistic infection: the infection must be adequately managed and the subject must be clinically stable. The investigator may discuss this issue with the Medical Lead. EXCLUSION CRITERIA: ANY subject who meets any of the following criteria is excluded from enrollment in this study: 1. Prior treatment with: - BRAF and/or MEK inhibitor(s) - Chemotherapy, immunotherapy, biologic therapy or chemoradiation with delayed toxicity within 21 days (or within 42 days if prior therapy contains nitrosourea or mitomycin C containing therapy) prior to enrollment - Chemotherapy or biologic therapy without evidence of delayed toxicity within 14 days prior to enrollment - Investigational product(s)(IP) within 30 days or 5 half-lives, whichever is longer, prior to enrollment - Subjects enrolled in France: Subject has participated in any study using an IP(s) within 30 days prior to enrollment in this study. 2. History of malignancy with confirmed activating RAS mutation at any time. NOTE: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, then those results must be used in assessing eligibility. 3. Prior radiotherapy less than 14 days prior to enrollment, except for WHO Grade1-4 glioma and ATC. Treatment-related AEs must have resolved prior to enrollment For WHO Grades 1, 2, 3, or 4 Glioma ONLY: Radiotherapy is not permitted within 3 months prior to enrollment (extended period of time of >3 months needed to prevent subjects with pseudo-progression from radiotherapy from being enrolled in the study). Subjects may be greater than or equal to 4 weeks from radiotherapy if a new lesion relative to the pre-radiation MRI develops outside the primary radiation field. Treatment-related AEs must have resolved prior to enrollment For ATC Only: Radiotherapy is not permitted within 7 days prior to enrollment. Treatment-related AE(s) must have resolved prior to enrollment. 4. Prior major surgery less than 14 days prior to enrollment. Any surgery-related AE(s) must have resolved prior to enrollment. 5. Prior solid organ transplantation or allogenic stem cell transplantation (ASCT) NOTE: Previous autologous BM transplant (ABMT) or autologous peripheral blood stem cell transplant (PBSCT) is permitted. 6. History of another malignancy NOTE: Subjects with another malignancy are eligible if: (a) disease-free for 3 years, or (b) have a history of completely resected non-melanoma skin cancer, and/or (c) have an indolent second malignancy(ies). Consult a Medical Lead if unsure whether second malignancies meet requirements specified above. 7. Presence of: - Brain metastases (except for subjects in the WHO Grade 1 or 2 Glioma or WHO Grade 3 or 4 Glioma histology cohorts) that are symptomatic or untreated or not stable for greater than or equal to 3 months (must be documented by imaging) or requiring corticosteroids. Subjects on a stable dose of corticosteroids >14 days and have not required treatment with enzyme-inducing anticonvulsants for >30 days prior to enrollment can be enrolled with approval of the Medical Lead. - Symptomatic or untreated leptomeningeal or spinal cord compression NOTE: Subjects who have been previously treated for these conditions and have stable CNS disease (documented by consecutive imaging studies) for >60 days, are asymptomatic and currently not taking corticosteroids, or have been on a stable dose of corticosteroids for at least 30 days prior to enrollment, are permitted. - Interstitial lung disease or pneumonitis - Any unresolved greater than or equal to Grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) toxicity from previous anti-cancer therapy at the time of enrollment, except alopecia or Grade 2 anemia NOTE: Subjects with MM who have less than Grade 2 peripheral neuropathy (per CTCAE v4.0) are permitted. -Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject s safety, obtaining informed consent or compliance to the study procedures 8. History of RVO 9. Clinically significant GI abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. For example, subjects should have no more than 50% of the large intestine removed and no sign of malabsorption (i.e., diarrhea). NOTE: If clarification is needed as to whether a condition will significantly affect the absorption of study treatments, contact the Medical Lead. 10. History or evidence of cardiovascular risk including any of the following: -Acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment -Clinically significant uncontrolled arrhythmias NOTE: Subjects with controlled atrial fibrillation for >30 days prior to enrollment are eligible. - Class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) criteria - Left ventricular ejection fraction (LVEF) below the institutional LLN NOTE: If a LLN does not exist at an institution, then use LVEF <50%. - Abnormal cardiac valve morphology (greater than or equal to Grade 2) documented by ECHO NOTE: Subjects with Grade 1 abnormalities (i.e., mild regurgitation/stenosis) may be entered on study. Subjects with moderate valvular thickening should NOT be enrolled. -Corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval (QTcB) greater than or equal to 480 msec - Intracardiac defibrillator - Treatment-refractory hypertension defined as a blood pressure (BP) >140/90 mmHg which may not be controlled by anti-hypertensive medication(s) and/or lifestyle modifications - Subjects enrolled in Germany: Subjects with a left bundle branch block (LBBB) are NOT eligible for inclusion in this study. 11. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result within 3 months prior to first dose of study treatment. NOTE: Subjects with positive Hepatitis C antibody due to prior exposure can be enrolled, only if a confirmatory negative Hepatitis C RNA polymerase chain reaction (PCR) test is obtained. 12. Current use of prohibited medication(s) or requirement for prohibited medications during study. NOTE: Use of anticoagulants such as warfarin is permitted; however, international normalization ratio (INR) must be monitored according to local institutional practice. 13. Clincally significant known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment, or excipients, or to dimethyl sulfoxide (structural component of dabrafenib). 14. Female subjects: Pregnant, lactating or actively breastfeeding Histology Specific Exclusion Criteria ATC 1. Presence of thyroid lymphomas, sarcomas, or metastatic disease from other sites of origin to the thyroid. 2. Has potentially curable ATC by surgical excision alone or subjects who have not received treatment that might be considered standard of care. BTC 1. Has biliary duct obstruction, unless a treatable, clinically relevant obstruction has been relieved by internal endoscopic drainage/stenting, palliative by-pass surgery or percutaneous drainage prior to enrollment. WHO Grade 1, 2, 3 or 4 Glioma 1. Prior treatment with enzyme-inducing anticonvulsants within 14 days prior to enrollment. 2. Radiotherapy treatment within 3 months prior to enrollment. NOTE: Extended period of time (>3 months) needed to prevent subjects with pseudo-progression from radiotherapy being enrolled in the study. Subjects may be greater than or equal to 2 weeks from radiotherapy if a new lesion relative to the pre-radiation MRI develops outside the primary radiation field. Treatment-related AEs must have resolved prior to enrollment.
-Signed, written informed consent
-Sex: male or female
-Age:greater than or equal to18 years of age at the time of providing informed consent.
-Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2.
-Must have advanced disease and no standard treatment options as determined by locally/regionally available standards of care and treating physician s discretion.
-Must have a BRAF V600E mutation-positive tumor as confirmed by an approved local laboratory or sponsor designated central reference laboratory.
-NOTE: All subjects must provide an archived or fresh tumor sample (for solid tumors) or a fresh BM aspirate and peripheral blood sample (for HCL and MM) for confirmation testing of the BRAF V600E mutation by a sponsor designated central reference laboratory using the a sponsor designated assay.
-ATC, BTC, GIST, NSGCT/NGGCT, and ASI ONLY: Must have at least one measurable lesion per RECIST 1.1 outside of a prior radiation field or within the field with evidence of progression.
-Able to swallow and retain orally administered medication.
-Female Subjects of Childbearing Potential: Subjects must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agrees to use highly effective contraception, as defined in Section 9.1, from 7 days prior to enrollment, throughout the treatment period and for 16 weeks following discontinuation of trametinib when taken in combination with dabrafenib, or for 2 weeks following discontinuation of dabrafenib monotherapy.
-Has adequate baseline organ function
-French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
Histology Specific Inclusion Criteria:
ATC
1. Histologically or cytologically confirmed, unresectable, metastatic ATC including ATC originating from within well-differentiated thyroid cancers or an ATC as part of a thyroid carcinoma of another histologic type.
NOTE: Squamoid differentiated subtype is not permitted. Diagnosis noted to be consistent with ATC with presence of thyroid mass is acceptable.
2. Has undergone evaluation via indirect or direct laryngoscopy to ensure patency of trachea/airway prior to enrollment if bulky thyroid/neck masses are present and/or airway obstruction is suspected.
3. Has undergone prior external beam radiotherapy and/or surgery to the primary tumor.
NOTE: Subjects with small primary tumor that has been totally removed by surgical excision whereby no radiotherapy was indicated (only metastatic lesions are manifested) or subjects with metastatic disease who do not require radiation or surgery to the neck mass will be eligible for participation in the study.
BTC
1. Histologically or cytologically confirmed, unresectable, metastatic or locally advanced or recurrent adenocarcinoma of the biliary tract or gallbladder
2. Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to treatment with a gemcitabine-based chemotherapy regimen.
GIST
1. Histologically confirmed diagnosis of c-Kit and PDGFRA wild-type GIST.
2. Must have metastatic or locally advanced, unresectable, or recurrent post-surgical disease.
3. Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to treatment with a TKI ( i.e., imatinib,sunitinib).
WHO Grade 1 and 2 Glioma
1. Histologically confirmed recurrent or progressive WHO Grade 1 or 2 glioma
2. For WHO Grade 1 glioma ONLY: To be considered eligible for study treatment, subject must:
a. Present with adequate level of favorable risk/benefit ratio including, but not limited to, the exhibited initial symptoms, AND
b. Be evaluated by a panel of neuro-oncologists and the Medical Lead prior to enrollment.
3. For WHO Grade 2 glioma ONLY: To be considered eligible for study treatment, subject must not be eligible for treatment with chemotherapy.
4. Must have measurable non-enhancing disease based on two-dimensional magnetic resonance imaging (MRI) with contrast assessments as per RANO response criteria,
NOTE: Enhancing disease is acceptable for pilocytic astrocytomas.
5.Must be receiving a stable or decreasing dose of corticosteroid treatment for 7 days prior to first dose of study treatment.
NOTE: Steroids dose is limited to up to 8 mg/day of dexamethasone or equivalent dose of steroid.
NOTE: Subjects are not required to be on corticosteroids to be eligible.
WHO Grade 3 or 4 Glioma
1. Histologically confirmed recurrent or progressive WHO Grade 3 or 4 glioma.
2. Had prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiation therapy.
NOTE: Subjects who have a WHO Grade 3 or 4 glioma for which chemotherapy and/or radiotherapy is not considered standard of care may remain eligible for the study. Consult the Medical Lead to discuss and determine if subject is eligible for enrollment.
3. Must have measurable disease at least 1 cm x 1 cm as per RANO response criteria
4. Must be receiving a stable or decreasing dose of corticosteroid treatment for 7 days prior to first dose of study treatments.
NOTE; Subjects are not required to be on corticosteroids to be eligible.
NSGCT/NGGCT
1. Histologically confirmed NSGCT/NGGCT.
2. Must have either:
-Refractory disease defined as disease progression during or relapsed after salvage high-dose chemotherapy (HDCT), or disease progression during cisplatin-based salvage chemotherapy.
OR
-Relapsed disease and ineligible for cisplatin-based salvage chemotherapy or HDCT.
ASI
1. Histologically confirmed, metastatic or locally advanced ASI, adenocarcinoma of the ampulla, or adenocarcinoma of the peri-ampulla.
2. Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to one line of chemotherapy.
HCL
1. Histologically confirmed diagnosis of HCL according to morphological and immunophenotypic criteria of WHO classification (WHO-2008) of lymphoid neoplasms.
- Refractory disease defined as no response or disease progression in less than or equal to 1 year following first-line treatment with a purine analog (i.e., pentostatin, cladribine or fludarabine)
- Relapsed disease defined as having relapsed following treatment with at least two prior treatments
3. Must have the presence of leukemic cells in the peripheral blood or BM aspirate or BM biopsy AND one or more of the following:
- Bulky/symptomatic splenomegaly
- Hemoglobin <10 g/dL
- Platelets <100 times 10(9)/L
- Absolute neutrophil count (ANC) <1 times 10(9)/L
4. For subjects with an opportunistic infection: the infection: the infection must be adequately managed and the subject must be clinically stable. The investigator may discuss this issue with the Medical Lead.
MM
1. Histologically confirmed secretory MM.
2. Has received at least 2 prior lines of therapy, such as prior treatment with a proteasome inhibitor and IMiD, and is now refractory or has demonstrated intolerance (despite standard measures of supportive care and dose reduction) to the most recent therapy received
3. Must have measurable disease of MM as defined by at least ONE of the
following:
- Serum M-protein greater than or equal to 1 g/dL (greater than or equal to10 g/L)
- Urine M-protein greater than or equal to 200 mg/24 hr
- Serum free light chain (FLC) assay: involved FLC level greater than or equal to 5 mg/dL (greater than or equal to 50 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65), or
- Biopsy proven plasmacytoma (measured within 28 days of Screening)
4. For subjects with an opportunistic infection: the infection must be adequately managed and the subject must be clinically stable. The investigator may discuss this issue with the Medical Lead.
EXCLUSION CRITERIA:
ANY subject who meets any of the following criteria is excluded from enrollment in this study:
1. Prior treatment with:
- BRAF and/or MEK inhibitor(s)
- Chemotherapy, immunotherapy, biologic therapy or chemoradiation with delayed toxicity within 21 days (or within 42 days if prior therapy contains nitrosourea or mitomycin C containing therapy) prior to enrollment
- Chemotherapy or biologic therapy without evidence of delayed toxicity within 14 days prior to enrollment
- Investigational product(s)(IP) within 30 days or 5 half-lives, whichever is longer, prior to enrollment
- Subjects enrolled in France: Subject has participated in any study using an IP(s) within 30 days prior to
enrollment in this study.
2. History of malignancy with confirmed activating RAS mutation at any time.
NOTE: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, then those results must be used in assessing eligibility.
3. Prior radiotherapy less than 14 days prior to enrollment, except for WHO Grade1-4 glioma and ATC. Treatment-related AEs must have resolved prior to enrollment
For WHO Grades 1, 2, 3, or 4 Glioma ONLY: Radiotherapy is not permitted within 3 months prior to enrollment (extended period of time of >3 months needed to prevent subjects with pseudo-progression from radiotherapy from being
enrolled in the study). Subjects may be greater than or equal to 4 weeks from radiotherapy if a new lesion relative to the pre-radiation MRI develops outside the primary radiation field. Treatment-related AEs must have resolved prior to enrollment
For ATC Only: Radiotherapy is not permitted within 7 days prior to enrollment. Treatment-related AE(s) must have resolved prior to enrollment.
4. Prior major surgery less than 14 days prior to enrollment. Any surgery-related AE(s) must have resolved prior to enrollment.
5. Prior solid organ transplantation or allogenic stem cell transplantation (ASCT)
NOTE: Previous autologous BM transplant (ABMT) or autologous peripheral blood stem cell transplant (PBSCT) is permitted.
6. History of another malignancy
NOTE: Subjects with another malignancy are eligible if: (a) disease-free for 3 years, or (b) have a history of completely resected non-melanoma skin cancer, and/or (c) have an indolent second malignancy(ies). Consult a Medical Lead if unsure whether second malignancies meet requirements specified above.
7. Presence of:
- Brain metastases (except for subjects in the WHO Grade 1 or 2 Glioma or WHO Grade 3 or 4 Glioma histology cohorts) that are symptomatic or untreated or not stable for greater than or equal to 3 months (must be documented by imaging) or requiring corticosteroids. Subjects on a stable dose of corticosteroids >14 days and have not required treatment with enzyme-inducing
anticonvulsants for >30 days prior to enrollment can be enrolled with approval of the Medical Lead.
- Symptomatic or untreated leptomeningeal or spinal cord compression
NOTE: Subjects who have been previously treated for these conditions and have stable CNS disease (documented by consecutive imaging studies) for >60 days, are asymptomatic and currently not taking corticosteroids, or have been on a stable dose of corticosteroids for at least 30 days prior to enrollment, are permitted.
- Interstitial lung disease or pneumonitis
- Any unresolved greater than or equal to Grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) toxicity from previous anti-cancer therapy at the time of enrollment, except alopecia or Grade 2 anemia
NOTE: Subjects with MM who have less than Grade 2 peripheral neuropathy (per CTCAE v4.0) are permitted.
-Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject s safety, obtaining informed consent or compliance to the study procedures
8. History of RVO
9. Clinically significant GI abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. For example, subjects should have no more than 50% of the large intestine removed
and no sign of malabsorption (i.e., diarrhea).
NOTE: If clarification is needed as to whether a condition will significantly affect the absorption of study treatments, contact the Medical Lead.
10. History or evidence of cardiovascular risk including any of the following:
-Acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment
-Clinically significant uncontrolled arrhythmias
NOTE: Subjects with controlled atrial fibrillation for >30 days prior to enrollment are eligible.
- Class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) criteria
- Left ventricular ejection fraction (LVEF) below the institutional LLN
NOTE: If a LLN does not exist at an institution, then use LVEF <50%.
- Abnormal cardiac valve morphology (greater than or equal to Grade 2) documented by ECHO
NOTE: Subjects with Grade 1 abnormalities (i.e., mild regurgitation/stenosis) may be entered on study. Subjects with moderate
valvular thickening should NOT be enrolled.
-Corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval (QTcB) greater than or equal to 480 msec
- Intracardiac defibrillator
- Treatment-refractory hypertension defined as a blood pressure (BP) >140/90 mmHg which may not be controlled by anti-hypertensive
medication(s) and/or lifestyle modifications
- Subjects enrolled in Germany: Subjects with a left bundle branch block (LBBB) are NOT eligible for inclusion in this study.
11. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result within 3 months prior to first dose of study treatment.
NOTE: Subjects with positive Hepatitis C antibody due to prior exposure can be enrolled, only if a confirmatory negative Hepatitis C RNA polymerase chain reaction (PCR) test is obtained.
12. Current use of prohibited medication(s) or requirement for prohibited medications
during study.
NOTE: Use of anticoagulants such as warfarin is permitted; however,
international normalization ratio (INR) must be monitored according to local
institutional practice.
13. Clincally significant known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment, or excipients, or to dimethyl sulfoxide (structural component of dabrafenib).
14. Female subjects: Pregnant, lactating or actively breastfeeding
Histology Specific Exclusion Criteria
1. Presence of thyroid lymphomas, sarcomas, or metastatic disease from other sites of origin to the thyroid.
2. Has potentially curable ATC by surgical excision alone or subjects who have not received treatment that might be considered standard of care.
1. Has biliary duct obstruction, unless a treatable, clinically relevant obstruction has been relieved by internal endoscopic drainage/stenting, palliative by-pass surgery or percutaneous drainage prior to enrollment.
WHO Grade 1, 2, 3 or 4 Glioma
1. Prior treatment with enzyme-inducing anticonvulsants within 14 days prior to enrollment.
2. Radiotherapy treatment within 3 months prior to enrollment.
NOTE: Extended period of time (>3 months) needed to prevent subjects with pseudo-progression from radiotherapy being enrolled in the study. Subjects may be greater than or equal to 2 weeks from radiotherapy if a new lesion relative to the pre-radiation MRI develops outside the primary radiation field. Treatment-related AEs must have resolved prior to enrollment.
Principal Investigator
Referral Contact
For more information: