E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
BRAF Mutant Metastatic Melanoma |
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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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027481 |
E.1.2 | Term | Metastatic melanoma |
E.1.2 | System Organ Class | 100000004864 |
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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 V600E metastatic melanoma treated with the oral agent dabrafenib.
The primary efficacy endpoint is presented in Section 7.2.1.1 of this protocol. |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives are:
• To assess the overall response rate in subjects with V600K mutant metastatic melanoma
•To assess progression free survival (PFS)
•To assess duration of response
•To assess overall survival (OS)
• To assess long-term (particularly 5-year) overall survival (OS)
The secondary efficacy endpoints are presented in Section 7.2.1.2 of this protocol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the study treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline Document Number CM2010/00010/03].
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Has signed informed consent.
2. Histologically confirmed metastatic melanoma (Stage IV), with BRAF mutation-positive (V600 E/K) melanoma as determined via central testing with a BRAF mutation assay.
3. Is treatment naïve or has received prior treatment for metastatic melanoma
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 prior to 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 |
Subjects meeting any of the following criteria must not be enrolled in the study. Deviations from the exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
1. Previous treatment with a BRAF or MEK inhibitor.
2. Known ocular or primary mucosal melanoma
3. 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 dabrafenib.
4. Current use of a prohibited medication or is expected to require any of these medications during treatment with GSK2118436 (See Section 6.2).
5. Current use of therapeutic warfarin.
•NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted.
6. 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.
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 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.
9. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
10. 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. History or evidence of brain metastases on MRI. If MRI is contraindicated, head CT with contrast may be performed to evaluate for brain metastases.
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.
15. History of alcohol or drug abuse within 6 months prior to Screening. |
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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 in V600 mutant melanoma, 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.5.1.1 | Timepoint(s) of evaluation of this end point |
The data cut for the primary analysis occurred in July 2011 |
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E.5.2 | Secondary end point(s) |
- Overall response rate in patients with V600K mutant melanoma
- Progression free survival 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.
- Overall survival, defined as the time from first dose until death due to any cause. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints were evaluated as part of the primary analysis in 2011. PFS, duration of response and OS will be evaluated again at the end of the study. |
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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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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 |
Australia |
France |
Germany |
Italy |
United States |
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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 |