Advanced non-small cell lung cancer and BRAF mutations MedDRA version: 21.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Tafinlar
Product Name: Dabrafenib
Product Code: GSK2118436
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Dabrafenib
CAS Number: 1195765-45-7
Current Sponsor code: GSK2118436
Othe
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects eligible for enrolment in the study and previously enrolled subjects crossing over from monotherapy to combination therapy must meet all of the following criteria: 1. Signed written informed consent; 2. Histologically- or cytologically-confirmed diagnosis of NSCLC stage IV (according to AJCC Staging 7th Edition); 3. For Cohorts A and B, documented tumor progression (based on radiological imaging) after receiving at least one prior approved platinum-based chemotherapy regimen for advanced stage/metastatic NSCLC. An alternate chemotherapeutic agent/regimen is an acceptable substitute in the event that the subject was intolerant to, or ineligible to receive platinum based chemotherapy. Subjects enrolled in Cohort B cannot have more than 3 prior systemic treatments for advanced stage/metastatic NSCLC (neoadjuvant and adjuvant therapies are not counted in number of prior regimens and maintenance therapy is not counted as a separate regimen). Subjects in Cohort C will be required to have not received prior systemic anti-cancer therapies for metastatic disease (i.e., dabrafenib/trametinib will be 1st line treatment for metastatic disease); 4. Measurable disease according to RECIST v1.1 [Eisenhauer, 2009]. Refer to Section 7.2.3.1 for the definition of a measurable lesion; 5. Male or female =18 years of age; 6. Anticipated life expectancy of at least 3 months; 7. Presence of a BRAF V600E mutation in lung cancer tissue. Mutation must be locally confirmed in a CLIA-certified laboratory (or equivalent). An adequate amount of umor tissue (archived tumor tissue, or fresh biopsy if archived tissue is not available) must be available at the time of enrolment for central validation of BRAF mutation see Section 7.1.1 for testing details and requirements regarding central confirmation); 8. Able to swallow and retain oral medication; 9. Women of childbearing potential must have a negative serum pregnancy test within 14 days before the first dose of study treatment and agree to use effective contraception, as defined in Section 7.4, during the study; NOTE: Oral contraceptives are not reliable due to potential drug-drug interaction with dabrafenib 10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 [Oken, 1982]; 11. Must have adequate baseline organ function as definedin Table 1: Hematologica ANC = 1.5 × 109/L Hemoglobin = 9 g/dL Platelet count = 100 x 109/L PT/INRb and PTT = 1.5 x ULN Hepatic Total bilirubin = 1.5 x ULN AST and ALT = 2.5 x ULN Renal (at least one of the following): Serum creatininec = 1.5 mg/dL Creatinine clearancec = 50 mL/min Cardiac Left Ventricular Ejection fraction (LVEF)d = LLN by ECHO 12. 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. 13. Previously tested for presence of EGFR and ALK mutations in lung cancer tissue confirmed in a CLIA-certified laboratory (or equivalent). Subjects with EGFR or ALK mutation are eligible if they have previously received EGFR or ALK inhibitor(s) respectively. 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 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 60
Exclusion criteria
Exclusion criteria: Subjects eligible for enrolment in the study and previously enrolled subjects crossing over from monotherapy to combination therapy must not meet any of the following criteria: 1. Previous treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119) prior to start of study treatment (Note: Prior treatment with dabrafenib is allowed for crossover subjects in Cohort A); 2. Anti-Cancer therapy including chemotherapy, radiation-therapy, immunotherapy, biologic therapy or major surgery within 14 days prior to start of study treatment (Note: Dabrafenib monotherapy within 14 days prior to starting combination therapy is allowed for crossover subjects in Cohort A); 3. Use of any investigational anti-cancer drug within 14 days or 5-half-lives (minimum 14 days), prior to start of study medication (Note: Dabrafenib monotherapy within 14 days prior to starting combination therapy is allowed for crossover subjects in Cohort A); 4. Current use of a prohibited medication or expected to require any of thesemedications during treatment with study treatment (See Section 6.2); 5. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia; 6. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the GlaxoSmithKlne (GSK) medical monitor for guidance to enrol the subject; 7. Known Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled; 8. History of another malignancy 1 cm in the longest dimension 10. A history or evidence of cardiovascular risk including any of the following: • Corrected QT (QTc) interval =480 msecs • History of acute coronary syndromes (including myocardial infarction or unstable angina) within 6 months prior to first dose of study treatment • Coronary angioplasty, or stenting within the past 24 weeks; • A history or evidence of current Class II, III, or IV heart failure as defined by the New York Heart Associati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the overall response rate (ORR) in subjects with stage IV BRAF V600E mutant non-small cell lung cancer administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C);Secondary Objective: • To assess progression-free survival (PFS), duration of response and overall survival (OS) in subjects with stage IV BRAF V600E mutant nonsmall cell lung cancer administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C) • To further characterize the safety and tolerability of dabrafenib when administered as a single agent and in combination with trametinib to subjects with stage IV BRAF V600E mutant nonsmall cell lung cancer • To characterize the population pharmacokinetics and identify important determinants of variability of dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C);Primary end point(s): ORR, which is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per RECIST v1.1 criteria;Timepoint(s) of evaluation of this end point: Scans are every 6 weeks from Week 1-36, then every 12 weeks after Week 36. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • PFS defined as the interval between first dose and the earliest date of disease progression or death due to any cause • Duration of response, defined for the subset of subjects with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression or death due to any cause • OS defined as the time from first dose until death due to any cause • Measurements used to evaluate safety will include physical and dermatological examinations, ophthalmic examination, vital signs, 12-lead ECGs, ECHO, clinical laboratory tests, and AEs • Dabrafenib and trametinib population pharmacokinetic parameters such as apparent clearance (CL/F) and volume of distribution (V/F), and relevant covariates which may influence exposure (e.g. age, weight, or disease related covariates);Timepoint(s) of evaluation of this end point: Scans are every 6 weeks from Week 1-36, then every 12 weeks after Week 36. | — |
Countries
France, Germany, Italy, Korea, Republic of, Netherlands, Norway, Spain, Taiwan, United Kingdom
Contacts
Public ContactMedica Information Services
Novartis Pharmaceuticals UK Limited
Outcome results
None listed