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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. (see Contacts and Locations)
Verified January 2015 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01336634
First received: April 7, 2011
Last updated: January 29, 2015
Last verified: January 2015
  Purpose

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.


Condition Intervention Phase
Cancer
Drug: Dabrafenib
Device: Trametinib
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • 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 administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C)


Secondary Outcome Measures:
  • 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 (Cohorts B and C)

  • 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 (Cohorts B and C)

  • 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 (Cohorts B and C)

  • Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: Approximately 2 years ] [ Designated as safety issue: Yes ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

  • Composite of PK parameters for Dabrafenib [ Time Frame: 3, 6, 12 and 18 weeks after onset of dosing ] [ Designated as safety issue: No ]
    Plasma concentration for Dabrafenib and derived 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 will be assessed for Cohort A and in combination with trametinib Cohorts B and C.

  • Safety as assessed by physical examination [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    A complete physical examination includes assessments of the head, eyes, ears, nose, throat, skin, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Pelvic and rectal assessments to investigate the presence of hyperproliferative skin and mucosal lesions are required at screening and at Discharge. Height and weight will also be measured and recorded (height is recorded at screening only). A brief physical examination will include assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).

  • Safety as assessed by dermatological examination [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    A full body dermatological examination will be performed by a dermatologist (or suitably qualified medical personnel) to identify abnormal skin lesions.

  • Safety as assessed by ophthalmic examination [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    Subjects treated with the dabrafenib and trametinib combination are required to have a standard ophthalmic examination performed by an ophthalmologist

  • Safety as assessed by vital signs [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    Vital sign measurements will include temperature, systolic and diastolic blood pressure and pulse rate.

  • Safety as assessed by Single 12-lead ECG [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    Single 12-lead ECGs will be obtained during the study using an ECG machine that automatically calculates the heart rate and measures RR, PR, QRS, QT, and QTc intervals. QRS axis will also be recorded.

  • Safety as assessed by echocardiography (ECHO) [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    Echocardiography scans will be performed.

  • Safety as assessed by clinical laboratory assessments [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
    A composite of laboratory perameters will be assessed.


Estimated Enrollment: 124
Study Start Date: June 2011
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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).
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.
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 C
Subjects enrolled in Cohort C 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
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)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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);
  • 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);
  • 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) >/=1.5x10^9/L Hemoglobin >/=9 g/dL Platelets >/=100x10^9/L Prothrombin time /International normalized ratio (INR) and partial thromboplastin time </=1.5xULN (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 Left ventricular ejection fraction >/= institutional lower limit of normal ECHO

  • 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) 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 GSK medical monitor for guidance to enrol the subject;
  • Known 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 C as well as subjects that crossover from monotherapy to combination therapy):
  • History of interstitial lung disease or pneumonitis
  • A history or current evidence of retinal vein occlusion (RVO).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01336634

Contacts
Contact: US GSK Clinical Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

  Show 71 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01336634     History of Changes
Other Study ID Numbers: 113928
Study First Received: April 7, 2011
Last Updated: January 29, 2015
Health Authority: Germany: Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte)
Norway: The Norwegian Medicines Agency (Statens legemiddelverk)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Japan: PMDA (Pharmaceuticals and Medical Devices Agency)
United States: Food and Drug Administration
France: French Agency for the Safety of Health Products (Agence nationale de sécurité du médicament et des produits de santé, ANSM)
Netherlands: Medicines Evaluation Board, MEB (College ter Beoordeling van Geneesmiddelen, CBG)
Korea: MFDS(Ministry of Food and Drug Safety)
Spain: Spanish agency of medicine and health care products (AEMPS: Agencia Española del Medicamento y Productos Sanitarios)
Italy: Italian medicines Agency (Agenzia Italiana del Farmaco, AIFA)

Keywords provided by GlaxoSmithKline:
BRAF V600E
GSK1120212
GSK2118436
Non-Small Cell Lung Cancer
trametinib
Oncology
dabrafenib

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Dabrafenib
Trametinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on February 26, 2015