A Phase II, Open-label, study in subjects with BRAF V600E-mutated rare cancers with several histologies to investigate the clinical efficacy and safety of the combination therapy of Dabrafenib and Trametinib
The goal of this clinical research study is to learn if the combination of dabrafenib and trametinib can help to control the disease in patients with cancers that are caused by a problem in a gene called BRAF V600E. The safety of the study drug combination will also be studied.
Disease Group: Biliary Tract
Treatment Agent: Dabrafenib
Treatment Location: Both at MDACC & and Other Sites
Primary To determine the overall response rate (ORR) of dabrafenib and trametinib anti-cancer combination therapy in subjects with rare BRAF V600E mutated solid tumors or hematologic malignancies. Secondary To determine the duration of response of dabrafenib in combination with trametinib in subjects with selected rare BRAF-mutated cancers. To determine progression-free survival (PFS) of dabrafenib in combination with trametinib in subjects with selected rare BRAF-mutated cancers. To determine overall survival (OS) of dabrafenib in combination with trametinib in subjects with selected rare BRAF-mutated cancers. To determine the safety of dabrafenib in combination with trametinib in subjects with selected rare BRAF-mutated cancers. Exploratory To identify candidate predictive and prognostic molecular features for each histology to characterize treatment-emergent malignancies and to characterize the mechanisms of underlying adverse events (AEs) of special interest. To investigate the relationship between plasma trametinib, dabrafenib, and dabrafenib metabolite concentrations, changes from baseline in tumor deaxyribonucleic acid (DNA), ribonucleic acid (RNA) or proteins and evaluate pharmacodynamic (PD) response. To evaluate changes from baseline in health-related quality of life (HRQOL) Pharmacogenetics (PGx): To investigate the relationship between genetic variants in host DNA and the pharmacokinetic (PK), safety, tolerability and efficacy of each therapeutic treatment.
IRB Review and Approval Date: 03/27/2014
Recruitment Status: Open
Projected Accrual: 225
1) Signed, written informed consent.
2) Sex: male or female
3) Age: >/= 18 years of age at the time of providing informed consent
4) Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2
5) Subject must have advanced disease and no standard treatment options as determined by locally/regionally available standards of care and treating physician's discretion.
6) Must have a BRAF V600E mutation-positive tumor as confirmed by an approved local laboratory or a 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 a sponsor designated assay.
7) Able to swallow and retain orally administered medication.
8) 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 from 7 days prior to enrollment, throughout the treatment period and for 4 months after the last dose of study treatment.
9) 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.
10) ATC COHORT: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.
11) ATC COHORT: 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.
12) ATC COHORT: 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.
13) ATC, BTC, GIST, NSGCT/NGGCT, and ASI ONLY: Must have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 outside of a prior radiation field or within the field with evidence of progression.
14) ATC COHORT: Has adequate baseline organ function as outlined: absolute neutrophil count (ANC) >/= 1.2x10^9/L; Hemoglobin >/= 9g/dL; Platelets >/= 75x10^9/L; prothrombin time (PT), partial thromboplastin time (PTT), international normalization ratio (INR) </=1.5 times upper limit of normal (ULN); Albumin >/= 2.5g/dL; Total bilirubin </= 1.5 times ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 2 times ULN without liver metastases, </= 2.5 times ULN if documented liver metastases; Creatinine </= 1.5 mg/dL OR calculated creatinine clearance or 24-hr urine creatinine clearance >/= 50mL/min; left ventricular ejection fraction (LVEF) >/= lower limit of normal (LLN) by echocardiogram (ECHO)
15) BTC COHORT: Histologically or cytologically confirmed, unresectable, metastatic or locally advanced or recurrent adenocarcinoma of the biliary tract or gallbladder
16) BTC COHORT:Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to treatment with a gemcitabine-based chemotherapy regimen.
17) BTC COHORT: Has adequate baseline organ function as outlined: ANC >/= 1.2x10^9/L; Hemoglobin >/= 9g/dL; Platelets >/= 75x10^9/L; PT,PTT, INR </=1.5 times ULN; Albumin >/= 2.5g/dL; Total bilirubin </= 3 times ULN if stable for 14 days prior to enrollment; ALT and AST </= 3 times ULN without liver metastases, </= 5 times ULN if documented liver metastases; Creatinine </= 1.5 mg/dL OR calculated creatinine clearance or 24-hr urine creatinine clearance >/= 50mL/min; LVEF >/= LLN by ECHO
18) GIST COHORT:Histologically confirmed diagnosis of c-Kit and platelet-derived grow factor receptor alpha (PDGFRA) wild-type GIST.
19) GIST COHORT:Must have metastatic or locally advanced, unresectable, or recurrent post-surgical disease.
20) GIST COHORT: Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to treatment with a tyrosine kinase inhibitor (TKI) (i.e., imatinib, sunitinib).
21) GIST and NSGCT/NGGCT COHORTS: Has adequate baseline organ function as outlined: ANC >/= 1.2x10^9/L; Hemoglobin >/= 9g/dL; Platelets >/= 75x10^9/L; PT,PTT, INR </=1.5 times ULN; Albumin >/= 2.5g/dL; Total bilirubin </= 2 times ULN; ALT and AST </= 2 times ULN without liver metastases, </= 2.5 times ULN if documented liver metastases; Creatinine </= 1.5 mg/dL OR calculated creatinine clearance or 24-hr urine creatinine clearance >/= 50mL/min; LVEF >/= LLN by ECHO
22) WHO Grade 1 and 2 Glioma COHORT:Histologically confirmed recurrent or progressive WHO Grade 1 or 2 glioma
23) WHO Grade 1 Glioma COHORT: To be considered eligible for study treatment, subject must: a. Present with adequate level of favourable risk/benefit ratio including, but not limited to, the exhibited initial symptoms, and b. Be evaluated by a panel of neuro-oncologists and the GSK Medical Monitor prior to enrollment.
24) WHO Grade 2 Glioma COHORT: To be considered eligible for study treatment, subject must not be eligible for treatment with chemotherapy.
25) WHO Grade 1 and 2 Glioma COHORT:Must have measurable non-enhancing disease based on two-dimensional magnetic resonance imaging (MRI) (with contrast) assessments, as per Response Assessment for Neuro-Oncology (RANO) response criteria. NOTE: Enhancing disease is acceptable for pilocytic astrocytomas.
26) WHO Grade 1 and 2 Glioma; and Grade 3 and 4 Glioma COHORTS: For subjects receiving a corticosteroid treatment, the subject 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.
27) WHO Grade 1 and 2 Glioma; and Grade 3 and 4 Glioma COHORTS: Has adequate baseline organ function as outlined: ANC >/= 1.2x10^9/L; Hemoglobin >/= 9g/dL; Platelets >/= 100 x10^9/L; PT,PTT, INR </=1.5 times ULN; Albumin >/= 2.5g/dL; Total bilirubin </= 2 times ULN; ALT and AST </= 3 times ULN; Creatinine </= 1.5 mg/dL OR calculated creatinine clearance or 24-hr urine creatinine clearance >/= 50mL/min; LVEF >/= LLN by ECHO
28) WHO Grade 3 and 4 Glioma COHORT:Histologically confirmed recurrent or progressive WHO Grade 3 or 4 glioma.
29) WHO Grade 3 and 4 Glioma COHORT: 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 Monitor to discuss and determine if subject is eligible for enrollment.
30) WHO Grade 3 and 4 Glioma COHORT:Must have measurable disease at least 1 cm x 1 cm using Modified Response Assessment for Neuro-Oncology (RANO) response criteria
31) NSGCT/NGGCT COHORT:Histologically confirmed NSGCT or NGGCT.
32) NSGCT/NGGCT COHORT:Must have either: 1) Refractory disease defined as disease progression during or relapsed after salvage high-dose chemotherapy (HDCT), or disease progression during cisplatin-based salvage chemotherapy OR 2) Relapsed disease and ineligible for cisplatin-based salvage chemotherapy or HDCT.
33) ASI COHORT: Histologically confirmed, metastatic or locally advanced ASI, adenocarcinoma of the ampulla, or adenocarcinoma of the peri-ampulla.
34) ASI COHORT: Must have progressed on or demonstrated intolerance (despite standard measures of supportive care and dose reduction) to one line of chemotherapy
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
1) Prior treatment with: a) BRAF and/or MEK inhibitor(s); b)
Chemotherapy, immunotherapy, biologic therapy or chemoradiation with
delayed toxicity within 21 days (or within 42 days if prior therapy
contains nitrosourea or mitomycin C) prior to enrollment; c)
Chemotherapy or biologic therapy without evidence of delayed toxicity
within 14 days prior to enrollment; d) 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 Grade 1-4 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 >/= 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 enrolment. 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 solid organ transplantation or allogenic stem cell transplantation (ASCT) NOTE: Previous autologous bone marrow transplant (ABMT) or autologous peripheral blood stem cell transplant (PBSCT) is permitted.
5) History of another malignancy. NOTE: Subjects with another malignancy are eligible if: (a) disease-free for 3 years, (b) had a history of completely resected non-melanoma skin cancer, and/or (c) have a indolent second malignancy(ies). Consult a GSK Medical Monitor if unsure whether second malignancies meet requirements specified above.
6) Presence of: a) 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 >/= 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 GSK Medical Monitor.
7) (6) continued: b) symptomatic or untreated leptomeningeal or spinal cord compression NOTE: Subjects who have been previously treated for these conditions and have stable central nervous system (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. c) interstitial lung disease or pneumonitis; d) Any unresolved >/= 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 </= Grade 2 peripheral neuropathy(per CTCAE v4.0) are permitted.e) 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 retinal vein occlusion (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 GSK Medical Monitor.
10) History or evidence of cardiovascular risk including any of the following: a) Acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment; b) Clinically significant uncontrolled arrhythmias NOTE: Subjects with controlled atrial fibrillation for >30 days prior to enrollment are eligible. c) Class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) criteria; d) Left ventricular ejection fraction (LVEF) below the institutional LLN NOTE: If a LLN does not exist at an institution, then use LVEF <50%. e) Abnormal cardiac valve morphology (>/= 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. f) Corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval (QTcB) >/= 480 msec;
11) cont. (10) g) Intracardiac defibrillator; h) 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; h) Subjects enrolled in Germany: Subjects with a left bundle branch block (LBBB) are NOT eligible for inclusion in this study.
12) 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.
13) Current use of prohibited medication(s) or requirement of prohibited medications during study. NOTE: Use of anticoagulants such as warfarin is permitted; however, international normalization ratio (INR) must be monitored according with local institutional practice.
14) Clinically significant known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment, or excipients, or to dimethyl sulfoxide and/or sulfonamides (structural component of dabrafenib)
15) Female subjects: Pregnant, lactating or actively breastfeeding
16) FOR ATC COHORT ONLY:Presence of thyroid lymphomas, sarcomas, or metastatic disease from other sites of origin to the thyroid.
17) FOR ATC COHORT ONLY:Has potentially curable ATC by surgical excision alone or subjects who have not received treatment that might be considered standard of care.
18) FOR BTC COHORT ONLY: 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.
19) FOR WHO Grade 1, 2, 3 and 4 Glioma COHORT ONLY: Prior treatment with enzyme-inducing anticonvulsants within 14 days prior to enrollment.
20) FOR WHO Grade 1, 2, 3 and 4 Glioma COHORT ONLY: 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 >/= 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.
21) Prior major surgery less than 14 days prior to enrollment. Any surgery-related AE(s) must have resolved prior to enrollment.