E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced non-small cell lung cancer and BRAF mutations |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To assess the overall response rate (ORR) in subjects with stage IV or relapsed BRAF V600E mutant non-small cell lung cancer administered GSK2118436 as a single agent. |
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E.2.2 | Secondary objectives of the trial |
• To assess progression free survival (PFS), duration of response and overall survival (OS) in subjects with stage IV or relapsed BRAF V600E mutant non-small cell lung cancer administered GSK2118436 as a single agent.
• To further characterize the safety and tolerability of GSK2118436 when administered as a single agent to subjects with stage IV or relapsed BRAF V600E mutant non-small cell lung cancer.
• To characterize the population pharmacokinetics of GSK2118436
and identify important determinants of variability. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Signed written informed consent;
2. Histologically- or cytologically-confirmed diagnosis of NSCLC Stage IV (according to AJCC Staging 7th Edition);
3. Documented tumor progression (based on radiological imaging) after receiving at least one prior approved platinum-based chemotherapy regimen for advanced stage/metastatic NSCLC;
Note: Additional lines of treatment including maintenance therapy with singleagents or combination regimens including investigational anti-cancer drugs are allowed
4. Measurable disease according to RECIST 1.1
5. Male or female ≥18 years of age;
6. Anticipated life expectancy of at least 3 months;
7. Presence of a V600E BRAF mutation in lung cancer tissue confirmed in a CLIA certified laboratory (or equivalent) (see Section 7.1.1 of study protocol for testing details, as well as additional requirements regarding central confirmation);
8. Able to swallow and retain oral medication;
9. Women with child-bearing potential must be willing to practice acceptable methods
of birth control during the study (See Section 7.4of study protocol);
NOTE: Oral contraceptives are not reliable due to potential drug-drug interaction with GSK2118436
10. Women of childbearing potential must have a menstrual history inconsistent with pregnancy and a negative serum pregnancy test within 14 days before the first dose of study medication and agree to use effective contraception, as defined in
Section 7.4 of the study protocol, during the study;
11. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2;
12. Must have adequate organ function as defined by the following baseline values:
• Absolute neutrophil count (ANC) ≥1.5x109/L
• Hemoglobin ≥9 g/dL
• Platelets ≥100x109/L
• Serum 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);
• Prothrombin time /International normalized ratio (INR) and partial
thromboplastin time ≤1.3xULN
• Left ventricular ejection fraction ≥ institutional lower limit of normal
13. 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. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Previous treatment with a BRAF or MEK inhibitor;
2. Anti-Cancer therapy including chemotherapy, radiation-therapy, immunotherapy, biologic therapy or major surgery within 14 days prior to start of study therapy;
3. Use of any investigational anti-cancer drug within 14 days or 5-half-lives prior to start of study therapy;
4. Current use of a prohibited medication or expected to require any of these medications during treatment with GSK2118436 (See Section 6.2 of study protocol);
5. 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;
6. 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;
7. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of HBV clearance may be enrolled;
8. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency;
9. History of another malignancy;
Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score ≤ 6, and 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 nontarget
lesions are eligible
10. 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 MRI), OR
• Asymptomatic and untreated but > 1 cm in the longest dimension
11. The following cardiac abnormalities:
• Corrected QT (QTc) interval ≥480 msecs
• History of acute coronary syndromes (including unstable angina) within the past 24 weeks
• Coronary angioplasty, or stenting within the past 24 weeks
• Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
• Abnormal cardiac valve morphology (≥ Grade 2) documented by
echocardiogram (subjects with Grade 1 abnormalities [ie, mild
regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study
• History of known arrhythmias (except sinus arrhythmia) within the past 24 weeks
12. Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension, etc), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures
required in the protocol;
13. Pregnant, lactating or actively breastfeeding females. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR, which is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per RECIST 1.1 criteria |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Scans are every 6 weeks from Week 1-36, then every 12 weeks after Week 36. |
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E.5.2 | Secondary end point(s) |
• PFS defined as the interval between first dose and the earliest date of disease progression or death due to any cause
• 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
• OS defined as the time from first dose until death due to any cause
• Measurements used to evaluate safety will include physical and dermatological examinations, vital signs, 12-lead ECGs, ECHO, clinical laboratory tests, and AEs
• GSK2118436 population PK parameters such as apparent clearance (CL/F) and volume of distribution (V/F), and relevant covariates which may influence exposure (e.g. age, weight, or disease related covariates) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Scans are every 6 weeks from Week 1-36, then every 12 weeks after Week 36. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Korea, Republic of |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will be considered complete when a minimum of 70% of subjects have died or five years have passed since the last subject was entered on the study, whichever comes first. Subjects who are still benefiting from GSK2118436 at the time of study completion may have the option to enter the rollover study, Protocol BRF114144, an open-label, rollover study of GSK2118436. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |