| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced BRAF V600-Mutation Positive Solid Tumors |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| 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 |
• 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 pharmacokinetics approach |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 ≥12 months and <18 years of age at the time of signing the informed consent form;
3. Recurrent, refractory 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;
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. Sexually active males, who do not agree to abstinence, must be willing to use a condom during intercourse while taking the study drug, and for 16 weeks after stopping treatment and should not father a child in this period.
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
9. Adequate renal and metabolic function defined as:
• Calculated eGFR (Schwartz formula, http://www.medcalc.com/pedigfr.html), or radioisotope GFR ≥90 mL/min/1.73m2; or
• A serum creatinine within the institutional reference range upper limit of normal (for age/gender, if available);
10. 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 disease under treatment involves the liver (requires radiographic confirmation of liver involvement)
11. 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 |
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, or (d) CLL in stable remission, 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, including major surgery, 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 Novartis Medical Lead;
17. Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory
evidence of Hepatitis B Virus clearance may be enrolled);
18. Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing;
19. Lactating females who are actively breast feeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Safety and tolerability of dabrafenib dose that achieves similar
exposures to the dabrafenib adult dose as assessed by number of
subjects with adverse events (AEs)
Safety and tolerability parameters will include recording of AEs, in Part 1
and Part 2 of the study.
2.Safety and tolerability of dabrafenib dose that achieves similar
exposures to the dabrafenib adult dose as assessed by change from
Baseline in ECG readings
Safety and tolerability parameters will include the electrocardiogram
(ECG) readings at Baseline and at end of Part 1 and Part 2 of the study.
3.Safety and tolerability of dabrafenib dose that achieves similar
exposures to the dabrafenib adult dose as assessed by change from
Baseline in ECHO findings
Safety and tolerability parameters will include recording of
echocardiogram (ECHO) at Baseline and at end of Part 1 and Part 2 of
the study.
4.Safety and tolerability of dabrafenib dose that achieves similar
exposures to the dabrafenib adult dose as assessed by change from
Baseline in laboratory values
Safety and tolerability parameters will include laboratory values at
Baseline and at end of Part 1 and Part 2 of the study.
5.Safety and tolerability of dabrafenib dose that achieves similar
exposures to the dabrafenib adult dose as assessed by change from
Baseline in vital signs
Safety and tolerability parameters will include vital signs at Baseline and
at end of Part 1 and Part 2 of the study.
6.Maximum concentration (Cmax) of dabrafenib dose(s)
To calculate the dabrafenib dose(s) for chronic dosing in pediatric
subjects (infants, children, and adolescents), the Cmax of dabrafenib
that achieves similar exposure to the dabrafenib adult dose will be
evaluated.
7.Area under the concentration-time curve over the dosing interval
(AUC(0-τ)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib
dose(s)
To calculate the dabrafenib dose(s) for chronic dosing in pediatric
subjects (infants, children, and adolescents) the AUC(0-τ) and AUC(0-
inf) of dabrafenib that achieves similar exposure to the dabrafenib adult
dose will be evaluated. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-5. : Up to 6 months
6-7. Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0,
0.5, 1, 2, 3, 4, 6 and 8 hours post dose. |
|
| E.5.2 | Secondary end point(s) |
1. Pre-dose (trough) concentration (Ctau)
2. The AUC(0-t) and AUC(0-tau) of dabrafenib and its metabolites.
Pharmacokinetic data will include area under the time-concentration
curve from time zero (pre-dose) to last time of quantifiable
concentration (AUC[0-t]), AUC(0-tau) of dabrafenib and its metabolites
(hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683],
and desmethyl-dabrafenib [GSK2167542]).
3. Apparent clearance following oral dosing (CL/F) (dabrafenib only)
4. Cmax of dabrafenib, and its metabolites
Pharmacokinetic data will include Cmax of dabrafenib and its
metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
5.Time from administration to Cmax (tmax) of dabrafenib and its
metabolites. Pharmacokinetic data will include tmax of dabrafenib and
its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib
[GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
6.Elimination half life (t½) of dabrafenib and its metabolites .
Pharmacokinetic data will include t½ of dabrafenib and its metabolites
(hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683],
and desmethyl-dabrafenib [GSK2167542]).
7.Longer term safety and tolerability of dabrafenib as assessed by
number of subjects with AEs. Safety and tolerability parameters will
include recording of AEs, in Part 1 and Part 2 of the study.
7.Longer term safety and tolerability of dabrafenib as assessed by
number of subjects with AEs. Safety and tolerability parameters will
include recording of AEs, in Part 1 and Part 2 of the study.
8.Longer term safety and tolerability of dabrafenib as assessed by
change from Baseline in ECG readings. Safety and tolerability parameters
will include the electrocardiogram (ECG) readings at Baseline and at end
of Part 1 and Part 2 of the study
9.Longer term safety and tolerability of dabrafenib as assessed by
change from Baseline in laboratory values. Safety and tolerability
parameters will include laboratory values at Baseline and at end of Part
1 and Part 2 of the study.
10.Longer term safety and tolerability of dabrafenib as assessed by
change from Baseline in vital signs. Safety and tolerability parameters
will include vital signs at Baseline and at end of Part 1 and Part 2 of the
study.
11.Overall tumor response of dabrafenib . Anti-tumor activity will be
assessed based on clinical evidence and the response evaluation criteria
in solid tumors (RECIST) version 1.1 criteria for solid tumors, response
assessment in neuro-oncology (RANO) criteria (glioma subjects) and
langerhans cell histiocytosis (LCH) scoring system.
12.Effect of age and weight on CL/F of dabrafenib. The CL/F data with
the effect of age and weight using a population pharmacokinetic
approach will be evaluated.
13.Effect of age and weight on volume of distribution (V/F) of
dabrafenib. The V/F data with the effect of age and weight using a
population pharmacokinetic approach will be evaluated.
14.Effect of age and weight on absorption rate (ka) of dabrafenib. The ka
data with the effect of age and weight using a population
pharmacokinetic approach will be evaluated.
15.Effect of age and weight on coefficients for significant covariates of
dabrafenib . The coefficients for significant covariates data with the
effect of age and weight using a population pharmacokinetic approach
will be evaluated. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 1-Predose, Day 15-Predose
2-6. Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0,
0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
7-11. Up to 6 months
12-15. Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0,
0.5, 1, 2, 3, 4, 6 and 8 hours post dose |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 |
| Study to determine safety, tolerability and pharmacokinetics |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 |
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 | 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 | 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 |
|
| 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
|
The study will be considered completed when the last subject enrolled
(without disease progression or withdraw from the study for another
reason) has been in the study for a minimum of 6 months AND, for
those subjects still benefiting from treatment, the rollover protocol is
open to enroll pediatric subjects. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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