| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid tumors with BRAF V600 gene mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced solid tumors with BRAF V600 gene mutation |
|
| 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 | 10028980 |
| E.1.2 | Term | Neoplasm |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The Primary objective of the trial:
To determine the safe and tolerable dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures to the dabrafenib adult dose,
in subjects with BRAF V600 mutation positive tumors |
|
| E.2.2 | Secondary objectives of the trial |
The Secondary objective of the trial:
• To characterize the pharmacokinetics of dabrafenib, and its metabolites
• To characterize the longer term safety and tolerability of dabrafenib
• To assess any preliminary anti-tumor activity of dabrafenib
• To determine the effect of age and weight on the pharmacokinetics of
dabrafenib using a population |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Written informed consent – a signed informed consent and/or assent (as age appropriate) will be obtained according to institutional guidelines;
2. Male or female between one month and <18 years of age (inclusive) at the time of signing the informed consent form;
3. Recurrent disease or progressive disease after having received at least one standard therapy for their disease;
NOTE: Subjects with metastatic (and surgically unresectable) melanoma can be enrolled for first-line treatment; Melanoma subjects with CNS involvement may be enrolled.
4. At least one evaluable lesion;
5. BRAF V600 mutation-positive tumor as confirmed in a CLIA-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing; centralized testing can confirm V600E and V600K mutations only);
6. Performance score of ≥50% according to the Karnofsky/Lansky performance status scale [Yates, 1908] (Appendix 3);
NOTE: Subjects with a performance status of ≤50% can be enrolled if the subject’s confinement to bed and inability to carry out activities is due solely to cancer-related
pain, as assessed by the investigator.
7. Females of child-bearing potential must be willing to practice acceptable methods of birth control (see Section 7.1). Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study medication;
8. Must have adequate organ function as defined by the following values:
Adequate bone marrow function defined as:
• Absolute neutrophil count (ANC) ≥1000/μL;
• Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)
• Platelets ≥75,000/μL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment
Adequate renal and metabolic function defined as:
• Calculated creatinine clearance (Cockcroft-Gault), calculated GFR (revised Schwartz formula), or radioisotope GFR ≥ 60 mL/min/1.73 m2; or
• A serum creatinine within the institutional reference range upper limit of normal (for age/gender, if available);
Adequate liver function defined as:
• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
• AST and ALT ≤2.5 x ULN; AST/ALT may be <5 x ULN at baseline if liver
metastases are present (requires radiographic confirmation of liver metastases)
Adequate cardiac function defined as:
• LVEF of either ≥50% by ECHO or greater than institutional LLN by ECHO (while not receiving medications for cardiac function)
• Corrected QT (QTcB) interval <450 msecs. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Part 2 ONLY: Previous treatment with dabrafenib, another RAF inhibitor, or a MEK inhibitor (exception: prior treatment with sorafenib is permitted);
2. Malignancy OTHER than the BRAF mutant malignancy under study
3. Had chemotherapy or radiotherapy within 3 weeks (or 6 weeks for nitrosoureas or mitomycin C) prior to administration of the first dose of study treatment;
4. The subject has received an investigational product within the following time period prior to the first dosing day in the current study: 28 days or 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is warranted by the data);
5. History of another malignancy;
Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score ≤ 6, and PSA < 10
ng/mL) requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from lung cancer target and nontarget lesions are eligible
6. Current use of a prohibited medication (Section 8.2) or herbal preparation or requires any of these medications during the study;
7. Unresolved toxicity greater than NCI CTCAE v4.0 [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of dabrafenib (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy);
8. Has leukaemia;
9. History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib and its excipients;
10. Autologous or allogeneic stem cell transplant within 3 months prior to enrolment
[NOTE: subjects with evidence of active graph versus host disease are excluded];
11. History of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongation;
12. Abnormal cardiac valve morphology (≥ grade 2) documented by echocardiogram
(NOTE: subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study);
13. Moderate valvular thickening;
14. Known, uncontrolled cardiac arrhythmias (except sinus arrhythmia) within the past 24 weeks;
15. Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease or uncontrolled infection), 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;
16. Presence of active GI disease or other condition (e.g., small bowel or large bowel resection) 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;
17. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of Hepatitis B Virus clearance may be enrolled);
18. Subjects with known G6PD deficiency;
19. Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing;
20. Lactating females who are actively breast feeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety, including adverse events (AEs), serious adverse events (SAEs), electrocardiogram (ECG), echocardiograms (ECHO), changes in laboratory values and vital signs Pharmacokinetics, including Cmax, AUC(0-t) and AUC(0-inf) of dabrafenib
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety endpoints will be evaluated throughout a subject’s participation in the study. Pharmacokinetic endpoints will be evaluated primarily over the first 15 days of treatment.
|
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics, including Ct (trough), Cmax, tmax and t½ of dabrafenib and its metabolites (GSK2285403, GSK2167542 and GSK2298683)
Safety, including AEs; ECG; changes in laboratory values and vital signs
Efficacy, including tumor response
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety endpoints will be evaluated throughout a subject’s participation in the study. Pharmacokinetic endpoints will be evaluated primarily over the first 15 days of treatment. |
|
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I/IIa Study to Determine the Safety, Tolerability and Pharmacokinetics in Pediatric subjects |
|
| 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 | Yes |
| 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 | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
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