| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic melanoma to the brain |
|
| 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 | 10025671 |
| E.1.2 | Term | Malignant melanoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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).
|
|
| 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) |
|
| 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 specific to each cohort:
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. (Refer to Section 5.3 Cautionary Medications).
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 [Oken, 1982].
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):
• Absolute neutrophil count (ANC) ≥1.5x109/L
• Haemoglobin ≥9 g/dL
• Platelets ≥100 x109/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
16.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 6.4.2.)
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. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
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 to determine eligibility.
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.
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.
|
|
| 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: 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, linear-accelerated-based radiosurgery, charged particles, and CyberKnife). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints:
• Overall response rate (ORR) in V600E mutation positive subjects, defined as the percentage of subjects with a confirmed investigator-assessed overall CR or PR by RECIST 1.1 criteria, for each cohort
• Duration of Intracranial Response for the subsets of V600E mutation positive subjects with confirmed intracranial CR or PR, defined as the time from first documented evidence of intracranial CR or PR until time of first documented intracranial disease progression or death due to any cause, for each cohort
• Duration of Overall Response for the subsets of V600E mutation positive subjects with confirmed overall CR or PR, defined as the time from first documented evidence of overall CR or PR until time of first documented disease progression or death due to any cause, for each cohort
Other secondary efficacy endpoints:
• OIRR in V600K mutation positive subjects for each cohort
• ORR in V600K mutation positive subjects, defined as the percentage of subjects
with a confirmed investigator-assessed overall CR or PR by RECIST 1.1 criteria, for each cohort
• Duration of Intracranial Response for the subset of V600K mutation positive subjects with confirmed intracranial CR or PR, defined as the time from first documented evidence of intracranial CR or PR until time of first documented intracranial disease progression or death due to any cause, for each cohort
• Duration of Overall Response for the subset of V600K mutation positive subjects with confirmed overall CR or PR, defined as the time from first documented evidence of overall CR or PR until time of first documented disease progression or death due to any cause, for each cohort
• Progression free survival (PFS) in V600E mutation positive subjects, defined as the interval between the date of the first dose of study treatment and the earliest date of intracranial or extracranial disease progression or death due to any cause, for each cohort
• PFS in V600K mutation positive subjects, defined as the interval between the date of the first dose of study treatment and the earliest date of intracranial or extracranial disease progression or death due to any cause, for each cohort
• Overall survival (OS) V600E mutation positive subjects, defined as the time from first dose of study treatment until death due to any cause, for each cohort
• OS in V600K mutation positive subjects, defined as the time from first dose of study treatment until death due to any cause, for each cohort
Exploratory efficacy endpoints:
Biomarker analysis.
Pharmacogenetics. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| 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 | 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 |
| Australia |
| Canada |
| United States |
|
| 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
|
| The study will be considered complete when 70% of subjects in Cohort A and 70% of subjects in Cohort B have died. |
|
| 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 |
Print
