Mutations of BRAF V600E have been identified at a high frequency in melanoma, PTC, colorectal and ovarian cancers. Such mutations have also been reported in some rare cancers such as anaplastic thyroid cancer, hairy cell leukemia, gastrointestinal stromal tumors, non-seminomatous/non-geminomatous germ cell tumors, biliary tract cancer, multiple myeloma, adenocarcinoma of the small intestine, World Health Organization Grade 1 and 2 gliomas and WHO Grade 3 and 4 gliomas. MedDRA version: 16.1 Le
Conditions
Interventions
Trade Name: Tafinlar
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: dabrafenib
CAS Number: 1195765-45-7
Current Sponsor code: GSK2118436
Other descriptive name: N-{3-[5-(2-Amino-4-pyrimidinyl
Sponsors
GlaxoSmithKline Research & Development Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: ALL subjects must meet Please refer to section 8 of the Protocol 01 for cohort specific criteria. all of the following inclusion criteria in order to be considered eligible for this study: 1. Signed, written informed consent 2. Sex: male or female 3. Age: > or = to 18 years of age at the time of providing informed consent 4. ECOG performance status: 0, 1 or 2 5. Subject must have histologically or cytologically confirmed advanced disease (as stated in the histology-specific inclusion/exclusion criteria [see Section 8]) and no available standard treatment options as determined by locally/regionally available standards of care. 6. BRAF V600E mutation-positive tumor: a. Local testing: Local BRAF mutation test results obtained by an approved local laboratory may be used to permit enrollment of subjects with positive results. Local BRAF mutation test results will be subject to central verification. b. Central testing: Local BRAF mutation test results will be confirmed by central testing in an approved, designated central reference laboratory by the THxID BRAF assay or an alternate GSK designated assay. NOTE: For central testing, FFPE core bone marrow (BM) biopsies are not acceptable from subjects in the MM cohort. 7. Able to swallow and retain orally administered medication. NOTE: Subject should not have any clinically significant gastrointestinal (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. 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 effective contraception, as defined in Section 10.1, 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 120 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: Please refer to section 8 of Protocol 01 for cohort specific 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) •Anti-cancer therapy (e.g., chemotherapy with delayed toxicity, immunotherapy, biologic therapy or chemoradiation) within 21 days (or within 42 days if prior nitrosourea or mitomycin C containing therapy) prior to enrolment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment •Investigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to enrolment 2. Previous major surgery within 21 days prior to enrollment 3. Prior extensive radiotherapy treatment within 21 days prior to enrollment 4. Prior solid organ transplantation or allogenic stem cell transplantation (ASCT) 5. History of: •Interstitial lung disease or pneumonitis •Another malignancy 6. Presence of: •cerebral metastases (except for subjects in the WHO Grade 1 or 2 Glioma or WHO Grade 3 or 4 Glioma histology cohorts; see histology-specific eligibility criteria) •symptomatic or untreated leptomeningeal or spinal cord compression •pre-existing >or= to Grade 2 peripheral neuropathy •unresolved treatment-related toxicity of >or= to Grade 2 (except alopecia) or toxicities listed in the general and histology-specific adequate organ function tables at the time of enrolment •Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures 7. History or current evidence/risk of RVO or CSR: •History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension or diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) •Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: •Evidence of new optic disc cupping •Evidence of new visual field defects •Intraocular pressure >21 mmHg 8. 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 •Class II or higher congestive heart failure as defined by the NYHA criteria (Appendix 2) •Left ventricular ejection fraction (LVEF) below the institutional LLN •Corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval (QTcB) >or+ to 480 msec •Intracardiac defibrillator and/or permanent pacemaker •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 •Known cardiac metastases 9. Current use of prohibited medication(s) or requirement of prohibited medications during study (see Section 11.2). 10. Positive for: •Hepatitis B surface antigen or Hepatitis C antibody •Human immunodeficiency virus (HIV); testing not required 11. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the ORR of dabrafenib and trametinib anti-cancer combination therapy in subjects with rare BRAF V600E mutated solid tumors or hematologic malignancies.;Secondary Objective: -To determine the duration of response of dabrafenib in combination with trametinib in subjects with selected rare BRAF-mutated cancers. -To determine PFS of dabrafenib in combination with trametinib in subjects with selected rare BRAF-mutated cancers. -To determine 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 tumors.;Primary end point(s): Tumor response as defined by: RECIST, version 1.1 for solid tumor histologies, Modified RANO and RANO for glioma or established response criteria for specific hematologic malignancies;Timepoint(s) of evaluation of this end point: Solid tumors – every 8 weeks until week 48 , then every 12 weeks until week 104, then institutional standard of care. Hematologic – HCL once blood counts are consistent with a complete response after 4 weeks, both a bone marrow biopsy and aspirate will be performed. If these tests are negative, a bone marrow biopsy and bone marrow aspirate will be performed every 6 months for 1 year, once a year for 2 years and then once every 2 years and at the time of relapse. MM - at Week 8, at the time of achieving a complete response or best response, and at the time of disease progression. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Duration of response -Investigator-assessed PFS -OS -Change from baseline in physical examination findings, vital signs, AEs, laboratory values and cardiac assessments;Timepoint(s) of evaluation of this end point: Duration of response - Solid– q 8 wks - wk 48, q 12 wks - wk 104, then institutional SoC. Hematologic–HCL once counts are consistent with CR after 4 wks, both a BM biopsy and aspirate. If negative, a BM biopsy and aspirate q 6 mths for 1 yr, q yr for 2 yrs, q 2 yrs and relapse MM-at Wk 8, at time of CR or best response, at PD •Investigator-assessed PFS - Solid tumors - q 8 wks - wk 48, q 12 wks - wk 104, then institutional SoC Hematologic – HCL once counts are consistent with CR after 4 wks, both a BM biopsy and aspirate. If negative a BM biopsy and aspirate q 6 mths for 1 yr, q yr for 2 yrs, q 2 yrs and relapse. MM - at Wk 8, time of CR or best response, at PD •OS q 3 mths after withdrawal of drug Change from baseline in PE, vital signs, AEs, labs and cardiac tests q 4 wks | — |
Countries
Austria, Belgium, Canada, Denmark, France, Germany, Italy, Korea, Democratic People's Republic of, Netherlands, Norway, Sweden, United States
Contacts
Public ContactClinical Trials Helpdesk
GlaxoSmithKline Research & Development Ltd
Outcome results
None listed