Clinical trial NCT01336634: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cancer
Keywords: BRAF V600E
trametinib
dabrafenib
GSK2118436
GSK1120212
Oncology
Non-Small Cell Lung Cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-04-18
Enrollment: 177
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months
Secondary outcomes:
measure: Progression Free Survival (PFS) Based on Local Investigator Assessment
timeFrame: 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
measure: Duration of Response (DoR) Based on Local Investigator Assessment
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: From study treatment start date until date of of death from any cause, assessed up to approximately 113 months
measure: Number of Participants With Treatment Emergent Adverse Events
timeFrame: From study treatment start date till 30 days safety follow-up, assessed up to approximately 81 months
measure: Apparent Clearance (CL/F) of Dabrafenib
timeFrame: Week 3, Week 6, Week 12 and Week 18
measure: Oral Volume of Distribution (V/F) of Dabrafenib
timeFrame: Week 3, Week 6, Week 12 and Week 18
measure: Apparent Clearance (CL/F) of Trametinib
timeFrame: Week 3, Week 6, Week 12 and Week 18
measure: Oral Volume of Distribution (V/F) of Trametinib
timeFrame: Week 3, Week 6, Week 12 and Week 18
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Orange
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Lebanon
country: United States
facility: Novartis Investigative Site
state: New Hampshire
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Columbus
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Pittsburgh
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Madison
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Caen Cedex 9
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Marseille Cedex 20
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Saint-Herblain Cedex
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Frankfurt/Main
country: Germany
facility: Novartis Investigative Site
city: Grosshansdorf
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Moers
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
city: Orbassano
country: Italy
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Tokyo
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
city: Pamplona
country: Spain
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.
citation: Li J, Sasane M, Zhang J, Zhao J, Ricculli ML, Yao Z, Redhu S, Signorovitch J. Is time to progression associated with post-progression survival in previously treated metastatic non-small cell lung cancer with BRAF V600E mutation? A secondary analysis of phase II clinical trial data. BMJ Open. 2018 Aug 17;8(8):e021642. doi: 10.1136/bmjopen-2018-021642.
citation: Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland A, Giannone V, D'Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4. Epub 2017 Sep 11.
citation: Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, Barlesi F, Kim TM, Mazieres J, Novello S, Rigas JR, Upalawanna A, D'Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016 Jul;17(7):984-993. doi: 10.1016/S1470-2045(16)30146-2. Epub 2016 Jun 6.
citation: Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, Souquet PJ, Smit EF, Groen HJ, Kelly RJ, Cho BC, Socinski MA, Pandite L, Nase C, Ma B, D'Amelio A Jr, Mookerjee B, Curtis CM Jr, Johnson BE. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016 May;17(5):642-50. doi: 10.1016/S1470-2045(16)00077-2. Epub 2016 Apr 11.