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.

Phase 2

Completed

Conditions: Cancer

Interventions: Drug: Dabrafenib
Drug: Trametinib

Registration Number: NCT01336634

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This was a Phase II, multicenter, 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. Central confirmation testing for the BRAF V600E mutation was performed and a sufficient number of subjects were enrolled with the intent of having at least 125 centrally confirmed subjects among the three cohorts.

Detailed Description: Subjects enrolled in Cohort A (Monotherapy Population) were required to have relapsed or progressed on at least one platinum based chemotherapy regimen prior to enrollment (i.e. dabrafenib was no less than second line treatment for metastatic disease). Additional lines of prior anti-cancer therapy were allowed. Subjects received dabrafenib as a single agent at the recommended dose of 150 mg twice daily. A 2 stage design with a planned sample size of 40 subjects was initially used for Cohort A.

Subjects enrolled in Cohort B (Combination Second-Line Population) were required to have relapsed or progressed on at least one platinum based chemotherapy prior to enrollment but did not receive more than 3 prior systemic anti-cancer therapies (i.e. dabrafenib/trametinib were second, third, or fourth line treatment for metastatic disease). Subjects received the recommended dose of both drugs (dabrafenib 150 mg twice daily and trametinib 2 mg once daily).

Subjects enrolled in Cohort C (Combination First-Line Population) did not receive prior systemic anti-cancer therapies for metastatic disease (i.e. dabrafenib/trametinib was first line treatment for metastatic disease). Subjects received the recommended dose of both drugs (dabrafenib 150 mg twice daily and trametinib 2 mg once daily).

Crossover: Subjects receiving and adequately tolerating dabrafenib as a single agent and who continued to meet the inclusion and exclusion criteria (including the additional criteria for combination therapy) had the option to crossover to dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination treatment at the time of radiologic disease progression with prior approval from a Medical Lead. If a subject was receiving less than 150 mg BID of dabrafenib at the time of the crossover, the subject was to continue at the lower dose of dabrafenib when initiating combination therapy.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 177

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort C - Double Combination (Dabrafenib+Trametinib) naive mBRAF V600E	Trametinib	Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.
Cohort A (Dabrafenib Monotherapy)	Dabrafenib	Participants received Dabrafenib 150mg BID and continued treatment until disease progression, death, or unacceptable adverse event. Participants receiving and adequately tolerating dabrafenib as a single agent and who continue to meet the inclusion and exclusion criteria had 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 medical monitor.
Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E	Dabrafenib	Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.
Cohort C - Double Combination (Dabrafenib+Trametinib) naive mBRAF V600E	Dabrafenib	Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.
Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E	Trametinib	Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months	ORR was defined as the percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) by investigator assessment as per RECIST v1 .1 criteria. Specifically, ORR = (number of subjects with a confirmed best overall response of CR or PR) divided by the total number of subjects in the corresponding analysis population.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) Based on Local Investigator Assessment	From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 113 months	Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
Duration of Response (DoR) Based on Local Investigator Assessment	From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 113 months	Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
Overall Survival (OS)	From study treatment start date until date of of death from any cause, assessed up to approximately 113 months	Overall Survival (OS) was defined as the time from first dose until death due to any cause. If a patient was not known to have died at the time of analysis cut-off, OS was censored at the date of last contact.
Number of Participants With Treatment Emergent Adverse Events	From study treatment start date till 30 days safety follow-up, assessed up to approximately 81 months	The distribution of adverse events (AE) was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Apparent Clearance (CL/F) of Dabrafenib	Week 3, Week 6, Week 12 and Week 18	Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology.
Oral Volume of Distribution (V/F) of Dabrafenib	Week 3, Week 6, Week 12 and Week 18	Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of dabrafenib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology.
Apparent Clearance (CL/F) of Trametinib	Week 3, Week 6, Week 12 and Week 18	Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of trametinib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology.
Oral Volume of Distribution (V/F) of Trametinib	Week 3, Week 6, Week 12 and Week 18	Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of trametinib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology.