E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic melanoma BRAF-positive |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027481 |
E.1.2 | Term | Metastatic melanoma |
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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 |
The primary objective of the study is to assess the overall response rate (ORR), defined as the proportion of subjects with investigator-assessed complete responses or partial responses, in subjects with metastatic melanoma treated with the oral agent GSK2118436 in subjects. |
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E.2.2 | Secondary objectives of the trial |
Efficacy The secondary efficacy objectives are: • To assess progression free survival (PFS) • To assess duration of response • To assess overall survival (OS). Safety The safety objective is to further characterize the safety and tolerability of GSK2118436 administered as a single agent for metastatic melanoma. Pharmacokinetics The pharmacokinetic objective is to characterize the population pharmacokinetics of GSK2118436 and identify important determinants of variability. BRAF Assay Development and Validation A BRAF mutation assay will be developed and validated. This assay will be used in the future to determine the specific BRAF mutational status in subjects with metastatic melanoma who may benefit from treatment with GSK118436. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has signed informed consent. 2. Histologically confirmed cutaneous metastatic melanoma (Stage IV), with BRAF mutation-positive (V600 E/K/D) melanoma as determined via central testing with a BRAF mutation assay. 3. Must have received at least one previous treatment for metastatic melanoma (i.e. chemotherapy, immunotherapy, prior targeted therapy, etc.). 4. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009]. 5. Age 18 years of age. 6. Able to swallow and retain oral medication. 7. Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study (See Section 7.3.2). 8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 [Oken, 1982]. 9. Must have adequate organ function as defined by the following baseline values: • Absolute neutrophil count (ANC) 1.5x109/L • Hemoglobin 9 g/dL • Platelets 75x109/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 method (refer to Section 12.4). Creatinine clearance must be > 50 mL/min. • Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) 1.3xULN • Left ventricular ejection fraction institutional lower limit of normal 10. Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment. 11. 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 |
1. Previous treatment with a BRAF or MEK inhibitor. 2. Cancer therapy (chemotherapy with delayed toxicity, radiation therapy, immunotherapy, biologic therapy, or major surgery) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks; or use of any investigational anti-cancer or other drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of GSK2118436. 3. Current use of a prohibited medication or requires any of these medications during treatment with GSK2118436 (See Section 6.2). 4. Current use of therapeutic warfarin. • NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted. 5. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] 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 permission to enroll the subject. 7. A history of 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 with permission of the GSK medical monitor. 8. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency. 9. History of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. 10. Presence of rheumatoid arthritis. 11. History or evidence of brain metastases on MRI. 12. 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 cardiac arrhythmias (except sinus arrhythmia) within the past 24 weeks. • Known cardiac metastases. 13. 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. 14. Pregnant or lactating females. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is overall response rate, which is defined as the percentage of subjects with a confirmed complete response (CR) or PR by investigator assessment as per RECIST 1.1 criteria |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 |