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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.

NCT01336634

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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.
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 113928
  • NCT ID: NCT01336634

Conditions

  • Cancer

Interventions

DrugSynonymsArms
DabrafenibCohort A

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalSubjects 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
  • Dabrafenib
Cohort BExperimentalSubjects 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.
  • Dabrafenib
Cohort CExperimentalSubjects 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
  • Dabrafenib

Eligibility 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants With Overall Response Rate (ORR) at the Date of Analysis
Time Frame:At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:ORR is defined as the percentage of par. with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per Response Evaluation Criteria In Solid Tumors evaluates the response on the basis of target and non-target lesions, and best over all response. The response rate was analyzed every 6 weeks (wks) after initiation of study treatment until Week 36 and then every 12 wks until discharge or crossover. Percentage of par. analyzed as number of par. having overall response on the date of analysis from Baseline multiply by 100. The Second Line Plus All Treated Population used for cohort A and B consisted of all par. in the All Treated Population who had received at least one line of prior anti-cancer therapy for advanced/metastatic disease. The First-Line All Treated Population used for cohort C consisted of all par. in the All Treated Population who had not received any prior anti-cancer therapy for advanced/metastatic disease.

Secondary Outcome Measures

Measure:Duration of Response (DoR) at the Date of Analysis
Time Frame:At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:DoR is defined for the subset of participants 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. The response was analyzed every 6 weeks after initiation of study treatment until Week 36 and then every 12 wks. Disease progression will be based on radiological assessments [magnetic resonance imaging (MRI) or computed tomography (CT)]. Confidence Intervals (CIs) estimated using the Brookmeyer Crowley method. Upper limit of confidence interval was not reached as data were not yet mature. A value of NA indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in that population (27 percent).
Measure:Progression Free Survival (PFS) at the Date of Analysis
Time Frame:At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. The target and non-target lesions were identified at time of screening and the same lesions were re-assessed by a contrast-enhanced brain magnetic resonance imaging (MRI) or Computed tomography (CT) every 6 wks after initiation of study treatment until Week 36 and then every 12 wks. CI estimated using the Brookmeyer Crowley method. A value of NA indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in the population (36 percent).
Measure:Overall Survival (OS) at the Date of Analysis
Time Frame:At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:OS defined as the time from first dose until death due to any cause. CI estimated using the Brookmeyer Crowley method. A value of NA indicates where no data is available or not able to determine the value. The upper bound of the 95 percent CI for the median was not reached due to insufficient event rates for Arm 2 (58 percent) and Arm 3 (28 percent).
Measure:Number of Participants With Abnormal Vital Signs Values
Time Frame:Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:Number of participants with abnormal values of vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and temperature were evaluated. Participants with worst case post-Baseline vital sign values were presented at the given timepoints. Only those participants with data available at the specified data points were analyzed. All treated population was used for monotherapy cohort which comprised of all participants in the monotherapy cohort who receive at least one dose of study treatment. HR: <60 bpm clinical concern-low; >100 bpm Clinical concern-high Temperature: <=35 °C clinical concern - low; >=38 °C clinical concern - high For SBP change from baseline, the following categories will be used: Grade 0: <120 mm Hg; Grade 1: >=120-<140 mmHg; Grade 2: >=140-<160 mmHg; Grade 3: >=160 mmHg; For DBP change from baseline, the following categories will be used: Grade 0: <80 mm Hg; Grade 1: >=80-<90 mmHg; Grade 2: 90-<100 mmHg; Grade 3: >=100mmHg
Measure:Number of Participants With Abnormal Electrocardiogram (ECG) Values
Time Frame:Week 3, Week 6, Week 15 and then every 9 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:Single measurements of 12-lead ECGs were obtained at given time points using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) interval. ECG values at worst case post-Baseline were categorized as 'clinically significant change from Baseline' and 'not a clinically significant change'.
Measure:Number of Participants With Abnormal Echocardiogram Findings
Time Frame:Week 6, Week 15 and then every 9 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:Echocardiography scans were obtained at given time points using an echocardiogram and the findings for left ventricular ejection fraction (LVEF) were obtained. LVEF values at worst case post-Baseline were recorded as any increase and any decrease values.
Measure:Number of Participants With Abnormal Clinical Chemistry Values
Time Frame:Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:Blood samples were collected from participants for evaluation of clinical chemistry parameters by worst case post-Baseline increase. The clinical chemistry parameters included creatinine, phosphate and high and low calcium, glucose, magnesium, potassium and sodium. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
Measure:Number of Participants With Abnormal Hematology Values
Time Frame:Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months
Safety Issue:
Description:Blood samples were collected from participants for evaluation of hematology parameters by worst case post-Baseline increase. The hematology parameters included leukocytes, neutrophils, platelets and high and low hemoglobin and lymphocytes. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
Measure:Number of Participants With AEs and Serious AEs (SAEs)
Time Frame:Up to Week 12 and then every 3 weeks up to follow up, for an average of 13.8 months
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function.
Measure:Apparent Clearance (CL/F) of Dabrafenib and Trametinib
Time Frame:Week 3, Week 6, Week 12 and Week 18
Safety Issue:
Description:Blood samples from participants were collected for population pharmacokinetic analysis including CL/F following oral dosing of dabrafenib and trametinib.
Measure:Volume of Distribution (V/F) of Dabrafenib and Trametinib
Time Frame:Week 3, Week 6, Week 12 and Week 18
Safety Issue:
Description:Blood samples from participants were collected for population pharmacokinetic analysis including V/F following oral dosing of dabrafenib and trametinib.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • BRAF V600E
  • trametinib
  • dabrafenib
  • GSK2118436
  • GSK1120212
  • Oncology
  • Non-Small Cell Lung Cancer

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