Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer.

This study is currently recruiting participants.
Verified March 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01336634
First received: April 7, 2011
Last updated: March 27, 2014
Last verified: March 2014

April 7, 2011
March 27, 2014
June 2011
September 2019   (final data collection date for primary outcome measure)
Overall response rate (ORR). [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
The overall response rate (ORR) (defined as the proportion of subjects with investigator-assessed confirmed complete response or partial response) in subjects with stage IV BRAF V600E mutant NSCLC that have progressed on at least one prior anticancer treatment for metastatic disease administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohort B)
Overall response rate (ORR) in V600E mutant non-small cell lung cancer subjects, which is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per RECIST 1.1 criteria [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01336634 on ClinicalTrials.gov Archive Site
  • Progression free survival (PFS). [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause 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 (Cohort B)
  • Duration of response. [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    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 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 (Cohort B)
  • Overall survival. [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    Overall survival defined as the time from first dose until death due to any cause 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 (Cohort B)
  • Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: Approximately 2 years ] [ Designated as safety issue: Yes ]
    To further characterize the safety and tolerability of dabrafenib when administered as a single agent and in combination with trametinib
  • Dabrafenib population pharmacokinetic (PK) parameters such as apparent clearance (CL/F), volume of distribution (V/F) and possible influencing factors such as age, weight or disease-related factors. [ Time Frame: 3, 6, 12 and 20 weeks after onset of dosing ] [ Designated as safety issue: No ]
    To characterize the population pharmacokinetics and identify important determinants of variability of dabrafenib as a single agent and in combination with trametinib
  • Progression free survival (PFS) defined as the interval between first dose and the earliest date of disease progression or death due to any cause [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
  • Overall survival defined as the time from first dose until death due to any cause [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
  • Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: Approximately 2 years ] [ Designated as safety issue: Yes ]
  • GSK2118436 population pharmacokinetic (PK) parameters such as apparent clearance (CL/F), volume of distribution (V/F) and possible influencing factors such as age, weight or disease-related factors. [ Time Frame: 3, 6, 12 and 20 weeks after onset of dosing ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer.
A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer

Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib administered as a single agent and in combination with trametinib in stage IV disease to subjects with BRAF mutant advanced non-small cell lung cancer. Subjects will receive dabrafenib 150 mg twice daily (BID) in monotherapy treatment and dabrafenib 150 mg bid and trametinib 2 mg once daily in combination therapy and continue on treatment until disease progression, death, or unacceptable adverse event.

Not Provided
Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Cancer
  • Drug: Dabrafenib
    Dabrafenib study treatment will be provided by GSK as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Each capsule contains 50 mg or 75 mg of free base (present as the mesylate salt).
  • Device: Trametinib
    Trametinib study treatment will be provided as 0.5 mg and 2 mg tablets. Each tablet will contain 0.5 mg or 2 mg of trametinib parent (present as the DMSO solvate)
  • Experimental: Cohort A
    Subjects will receive dabrafenib 150mg BID and will continue on treatment until disease progression, death, or unacceptable adverse event. Subjects receiving and adequately tolerating dabrafenib as a single agent and who continue to meet the inclusion and exclusion criteria will have the option to switch to dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination treatment within 4 weeks of radiologic disease progression with prior approval from a GSK medical monitor
    Intervention: Drug: Dabrafenib
  • Experimental: Cohort B
    Subjects enrolled in Cohort B will receive dabrafenib 150 mg BID in combination with trametinib 2 mg once daily and will continue on treatment until disease progression, death, or unacceptable adverse event.
    Interventions:
    • Drug: Dabrafenib
    • Device: Trametinib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
100
September 2019
September 2019   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Signed written informed consent;
  • Histologically or cytologically confirmed non-small cell cancer of the lung (NSCLC) stage IV (accordingto AJCC Staging 7th Edition);
  • 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);
  • Measurable disease according to Response Evaluation Criteria in Solid Tumors [RECIST 1.1];
  • At least 18 years of age;
  • Anticipated life expectancy of at least three months;
  • 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 tumor 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;
  • Able to swallow and retain oral medication;
  • 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 during the study; NOTE: Oral contraceptives are not reliable due to potential drug-drug interaction with dabrafenib.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2;
  • Must have adequate organ function as defined by the following baseline values:

Absolute neutrophil count (ANC) >/=1.5x109/L Hemoglobin >/=9 g/dL Platelets >/=100x109/L Prothrombin time /International normalized ratio (INR) and partial thromboplastin time </=1.3xULN (Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to starting study treatment.) Total bilirubin </=1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 2.5xULN Serum creatinine </=1.5 mg/dL (if serum creatinine is >1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault; creatinine clearance must be > 50 mL/min); creatinine clearance should be >/= 50 mL/min Prothrombin time /International normalized ratio (INR) and partial thromboplastin time </=1.3xULN Left ventricular ejection fraction >/= institutional lower limit of normal

  • 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
  • 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.

Exclusion Criteria:

  • 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);
  • 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);
  • 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);
  • Current use of a prohibited medication or expected to require any of these medications during treatment with study treatment.
  • 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;
  • 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;
  • Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled;
  • History of another malignancy < 3 years prior to starting study treatment or any malignancy with confirmed activating RAS-mutation; Exceptions: Subjects with any of the following malignancies within 3 years (does not include malignancies with confirmed activating RAS-mutation) are eligible: (a) a history of completely resected skin cancer, (b) successfully treated in situ carcinoma, (c) chronic lymphocytic lymphoma (CLL) in stable remission, or (d) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score <= 6, and prostate specific antigen [PSA] < 10 ng/mL) requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible
  • Subjects with brain metastases are excluded if their brain metastases are:
  • Symptomatic OR
  • Treated (surgery, radiation therapy) but not clinically and radiographically stable 3 weeks after local therapy(as assessed by contrast enhanced magnetic resonance imaging [MRI] or computed tomography [CT]), OR
  • Asymptomatic and untreated but >1 cm in the longest dimension
  • 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 Association (NYHA) guidelines; Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mmHg which cannot be controlled by antihypertensive therapy; Abnormal cardiac valve morphology ( >=Grade 2) documented by echocardiogram (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; Patients with intra-cardiac defibrillators A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to randomization are eligible.

Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension, etc.), psychological, familial, sociological, or geographical conditions that interfere with the subject's safety or obtaining informed consent or do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol;

  • Pregnant, or actively breastfeeding females.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
  • Additional Exclusion Criteria for dabrafenib and trametinib combination therapy (Cohort B and subjects that crossover from monotherapy to combination therapy):
  • History of interstitial lung disease or pneumonitis
  • A history or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED):

Presence of predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or

Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or RPED such as:

Evidence of new optic disc cupping; Evidence of new visual field defects on automated perimetry; Intraocular pressure >21 mmHg as measured by tonography

Both
18 Years and older
No
Contact: US GSK Clinical Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
United States,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Norway,   Spain,   Taiwan,   United Kingdom
 
NCT01336634
113928
Yes
GlaxoSmithKline
GlaxoSmithKline
Not Provided
Study Director: GSK Clinical Trials GlaxoSmithKline
GlaxoSmithKline
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP