E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
BRAF V600E or V600K mutation-positive metastatic melanoma to the brain |
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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 | LLT |
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 of the study is to assess the overall intracranial response rate (OIRR), defined as the proportion of subjects with confirmed complete intracranial responses (CRs) or partial intracranial responses (PRs) assessed by investigators in each of two cohorts of subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain treated with oral GSK2118436: • Cohort A: Subjects who have not received any local therapy for brain metastases • Cohort B: Subjects who have failed prior local therapy for brain metastases including but not restricted to brain surgery, Whole Brain Radiotherapy (WBRT) or Stereotactic Radiosurgery (SRS e.g. gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife). |
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E.2.2 | Secondary objectives of the trial |
• To estimate the overall response rate (ORR) • To estimate duration of response of intracranial disease and overall response • To estimate progression-free survival (PFS) • To estimate overall survival (OS) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Cohort A: 1a. No prior local therapy for brain metastases, 2a. Subjects who are receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 3 weeks prior to first dose of study treatment, 3a. No prophylactic or preventive anti-epileptic therapy. 2.Cohort B: 1b. Progression of existing lesions based on RECIST 1.1 (> 20% increase in longest diameter on baseline scan) or new lesions following local therapy for brain metastases including but not restricted to brain surgery, Whole Brain Radiotherapy (WBRT) or Stereotactic Radiosurgery (SRS e.g. gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife), 2b. Subjects who are receiving concomitant corticosteroids must be on a stable dose for at least 2 weeks prior to first dose of study treatment. (Refer to Section 5.3 Cautionary Medications), 3b. Prophylactic or preventive anti-epileptic therapy is allowed (Refer to Section 5.3 Cautionary Medications). Subjects eligible for enrolment in the study must meet all of the following criteria: General: 4.Signed written informed consent. 5.Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation as determined by central testing. 6.Up to two previous treatment regimens for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy. 7.At least one measurable intracranial target lesion for which all of the following criteria have to be met: previously untreated or progressive according to RECIST 1.1 (≥ 20% increase in longest diameter on baseline scan) after previous local therapy, immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy, largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced MRI, for target lesions (for definition see Section 6.1.1) with diameter of > 0.5 cm but ≤ 1 cm documented, measurement by neuroradiologist is required, for all lesions with diameter of ≥ 3 cm but ≤ 4 cm documented measurement by neuroradiologist is required. 8.Time interval between last day of previous anti-tumour systemic treatment and first dose of GSK2118436: 14 days elapsed from last treatment with surgery, SRS or gamma knife, 28 days elapsed from last treatment with WBRT, ≥28 days or five half-lives (whichever is longer) have elapsed from last dose of approved or investigational chemo-, cytokine-, immune-, biological-, or vaccine-therapy. 8.Age ≥18 years of age. 9.Able to swallow and retain oral medication 10.Must be able to understand and comply with protocol requirements and instructions. 11.Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 12.Must have adequate organ function as defined by the following screening values (Retesting of borderline screening organ function and treatment with blood transfusions, growth factors etc. will be allowed): ANC ≥1.5x109/L, Haemoglobin ≥9 g/dL, Platelets ≥100 x109/L, •Serum bilirubin ≤1.5 x ULN, AST and ALT ≤ 2.5xULN, Serum Creatinine ≤1.5 mg/dL (If serum creatinine is >1.5 mg/dL, Creatinine clearance must be > 50 mL/min, PT/INR and PTT ≤1.3xULN, Left ventricular ejection fraction ≥ institutional lower limit of normal 16.Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study 17.Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment. 18.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.Neurological symptoms related to brain metastasis. 2.Previous treatment with a BRAF or MEK inhibitor. 3.Current or expected use of a prohibited medication (Refer to Section 5.2 Prohibited Medications including enzyme inducing antiepileptic drugs [EIAEDs]) during treatment with GSK2118436. 4.Presence of leptomeningeal disease or primary dural metastases. 5.Known allergies against contrast agents required for magnetic resonance imaging (MRI) of intracranial lesions. 6.Current use of therapeutic warfarin.(NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted). 7.Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia. 8.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 enrol the subject. 9.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. 10.Acute infection requiring intravenous antibiotics. 11.A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency. 12.History of another malignancy. Exception: (a) a history of completely resected non-melanoma skin cancer, (b) successfully treated in situ carcinoma, (c) CLL in stable remission, or (d) indolent prostate cancer requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from melanoma target and non-target lesions are eligible. 13.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 [i.e., 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. 14.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. 15.Pregnant, lactating or breastfeeding females. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is the overall intracranial response rate (OIRR), which is defined as the percentage of subjects whose intracranial response is a confirmed Complete Response (CR) or Partial response (PR) assessed by Investigators using modified RECIST 1.1 criteria for each of the following: • Cohort A: Subjects who are treatment-naive for brain metastases • Cohort B: Subjects who have failed prior local therapy for brain metastases including but not restricted to brain surgery, Whole Brain Radiotherapy (WBRT) or Stereotactic Radiosurgery (SRS e.g. gamma knife, linearaccelerated- based radiosurgery, charged particles, and CyberKnife). |
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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 | Yes |
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 | 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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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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Lo studio si considerera` completato quando il 70% dei soggetti della Coorte A e il 70% dei soggetti della Coorte B saranno deceduti, ritirati prematuramente dallo studio o persi al follow-up. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |