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 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: 1139282011-001161-41CDRB436E2201
• Study Type: interventional
• Target: 177
• Locations: 11 countries
• Sites: 50

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.

Conditions

Cancer

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR)

  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.

  From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months

Secondary Outcomes (8)

• 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

• 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

• Overall Survival (OS)

  From study treatment start date until date of of death from any cause, assessed up to approximately 113 months

• 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

• Apparent Clearance (CL/F) of Dabrafenib

  Week 3, Week 6, Week 12 and Week 18

Study Arms (3)

Cohort A (Dabrafenib Monotherapy)

EXPERIMENTAL

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.

Drug: Dabrafenib

Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E

EXPERIMENTAL

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.

Drug: Dabrafenib; Drug: Trametinib

Cohort C - Double Combination (Dabrafenib+Trametinib) naive mBRAF V600E

EXPERIMENTAL

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.

Drug: Dabrafenib; Drug: Trametinib

Interventions

Dabrafenib DRUG

Dabrafenib study treatment was provided 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)

Also known as: DRB436, GSK2118436

Cohort A (Dabrafenib Monotherapy); Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E; Cohort C - Double Combination (Dabrafenib+Trametinib) naive mBRAF V600E

Trametinib DRUG

Trametinib study treatment was provided as 0.5 mg and 2 mg tablets. Each tablet contained 0.5 mg or 2 mg of trametinib parent (present as the dimethyl sulfoxide solvate)

Also known as: TMT212, GSK1120212

Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E; Cohort C - Double Combination (Dabrafenib+Trametinib) naive mBRAF V600E

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (50)

Novartis Investigative Site

Los Angeles, California, 90033, United States

Location

Novartis Investigative Site

Orange, California, 92868, United States

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Novartis Investigative Site

Aurora, Colorado, 80045, United States

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Novartis Investigative Site

Tampa, Florida, 33612, United States

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Novartis Investigative Site

Baltimore, Maryland, 21231, United States

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Novartis Investigative Site

Boston, Massachusetts, 02114, United States

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Novartis Investigative Site

Boston, Massachusetts, 02215, United States

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Novartis Investigative Site

Ann Arbor, Michigan, 48109-5848, United States

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Novartis Investigative Site

St Louis, Missouri, 63110, United States

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Novartis Investigative Site

Lebanon, New Hampshire, 03756, United States

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Novartis Investigative Site

New York, New York, 10065, United States

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Novartis Investigative Site

Columbus, Ohio, 43210, United States

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Novartis Investigative Site

Pittsburgh, Pennsylvania, 15232, United States

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Novartis Investigative Site

Seattle, Washington, 98109, United States

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Novartis Investigative Site

Madison, Wisconsin, 53792, United States

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Novartis Investigative Site

Caen, 14033, France

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Novartis Investigative Site

Lille, 59037, France

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Novartis Investigative Site

Marseille, 13915, France

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Novartis Investigative Site

Pierre-Bénite, 69495, France

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Novartis Investigative Site

Saint-Herblain, 44805, France

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Novartis Investigative Site

Strasbourg, 67091, France

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Novartis Investigative Site

Toulouse, 31059, France

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Novartis Investigative Site

Villejuif, 94805, France

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Novartis Investigative Site

Frankfurt am Main, 60487, Germany

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Novartis Investigative Site

Großhansdorf, 22927, Germany

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Novartis Investigative Site

Heidelberg, 69126, Germany

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Novartis Investigative Site

Moers, 47441, Germany

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Novartis Investigative Site

Milan, 20133, Italy

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Novartis Investigative Site

Milan, 20141, Italy

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Novartis Investigative Site

Orbassano, 10043, Italy

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Novartis Investigative Site

Osaka, 534-0021, Japan

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Novartis Investigative Site

Tokyo, 104-0045, Japan

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Novartis Investigative Site

Amsterdam, 1081, Netherlands

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Novartis Investigative Site

Groningen, 9713, Netherlands

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Novartis Investigative Site

Oslo, 0310, Norway

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Novartis Investigative Site

Seoul, 110-744, South Korea

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Novartis Investigative Site

Seoul, 120-752, South Korea

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Novartis Investigative Site

Seoul, 135-710, South Korea

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Novartis Investigative Site

Barcelona, 08025, Spain

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Novartis Investigative Site

Barcelona, 08036, Spain

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Novartis Investigative Site

Madrid, 28006, Spain

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Novartis Investigative Site

Madrid, 28034, Spain

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Novartis Investigative Site

Málaga, 29010, Spain

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Novartis Investigative Site

Pamplona, 31008, Spain

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Novartis Investigative Site

Seville, 41013, Spain

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Novartis Investigative Site

Taichung, 40705, Taiwan

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Novartis Investigative Site

Taipei, Taiwan

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Novartis Investigative Site

London, SW3 6JJ, United Kingdom

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Novartis Investigative Site

Oxford, OX3 7LJ, United Kingdom

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Novartis Investigative Site

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 34225229 DERIVED

• 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.

  PMID: 30121602 DERIVED

• 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.

  PMID: 28919011 DERIVED

• 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.

  PMID: 27283860 DERIVED

• 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.

  PMID: 27080216 DERIVED

MeSH Terms

Conditions

Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2011
• First Posted: April 18, 2011
• Study Start: August 5, 2011
• Primary Completion: October 1, 2015
• Study Completion: January 7, 2021
• Last Updated: April 4, 2022
• Results First Posted: December 7, 2017

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

ES (7); JP (2); GB (3); NL (2); NO (1); FR (8); IT (3); US (15); TW (2); DE (4); KR (3)