E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
BRAF mutation positive metastatic melanoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025670 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025671 |
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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 for this study is to establish the superiority of GSK2118436 over DTIC with respect to progression-free survival for subjects with BRAF mutation positive metastatic melanoma |
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E.2.2 | Secondary objectives of the trial |
1.Efficacy:•to compare overall survival between treatment groups •to assess the progression-free survival of subjects in the DTIC treatment group after initial progression and subsequent cross-over to GSK2118436 •to compare best overall response rate between treatment groups • to assess duration of response in subjects receiving GSK2118436 • to further validate a BRAF mutation assay. 2. Safety: •to assess the rate of non-melanoma skin lesions and other second malignancies in both treatment groups •to further characterize the safety, and tolerability of GSK2118436 administered as a single agent for BRAF mutation positive metastatic melanoma •to evaluate the qualitative and quantitative toxicities between treatment arms. 3. Pharmacokinetics The pharmacokinetic objective is to characterize the population pharmacokinetics of GSK2118436 and identify important determinants of variability. Per ulteriori dettagli, consultare il protocollo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has provided signed informed consent. 2. Histologically confirmed advanced (unresectable Stage III) or metastatic melanoma (Stage IV) and BRAF mutation-positive (V600 E) melanoma as determined via central testing with a BRAF mutation assay. 3. Are treatment na�ve for advanced (unresectable) or metastatic melanoma, with the exception of IL-2 which is allowed. 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. Additionally, women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment. 8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 9. Must have adequate organ function as defined by the following screening values (Retesting of borderline screening organ function. will be allowed. Treatment with transfusion, growth factors to meet eligibility criteria will not be allowed):•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 method. 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. 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 for metastatic melanoma, including treatment with BRAF or MEK inhibitor.2. Known ocular or primary mucosal melanoma.3. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, or surgery.4. Use of any investigational anti-cancer or other drug within 28 days or 5 half-lives,whichever is longer, preceding the first dose of GSK2118436.5. Current use of a prohibited medication or is expected to require any of these medications during treatment with GSK2118436.6. Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. 7. 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 8. A history of Human Immunodeficiency Virus (HIV) infection 9. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency 10. A 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 11. Evidence of active CNS disease (radiographically unstable, symptomatic lesions). However prior treatment with stereotactic radiosurgery (SRS) or surgical resection is allowed if the subject remains without evidence of disease progression in the brain ≥3 months, and has been off corticosteroids for ≥3 weeks. Whole brain radiotherapy is not allowed except in those subjects who have had definitive resection or SRS of all radiographically detectable parenchymal lesions. 12. History of alcohol or drug abuse within 6 months prior to Screening 13. 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. 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, mildregurgitation/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. 15. Pregnant or lactating female. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is progression free survival (PFS). For this study, PFS is defined as the time from randomization until the first date of either objective disease progression or death due to any cause. |
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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 | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 | 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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Lo studio sara` considerato completato quando il 70% dei soggetti e` deceduto. |
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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 |