| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children and Adolescents with Cancers Harboring V600 mutations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Children and Adolescents with Cancers Harboring V600 mutations |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029260 |
| E.1.2 | Term | Neuroblastoma |
| 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 |
| To determine the safe and tolerable trametinib dose(s) for chronic continuous daily dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures (trough concentration [Ct]) to the recommended adult dose. |
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the pharmacokinetics of trametinib
- To characterize the safety and tolerability of trametinib
- To assess any preliminary anti-tumor activity of trametinib
- To determine the effect of covariates such as age and weight on the pharmacokinetics of trametinib using a population pharmacokinetics approach
-To characterize the pharmacokinetics of trametinib and dabrafenib when administered in combination
-To characterize the safety and tolerability of trametinib and dabrafenib when administered in combination
- To determine the safe and tolerable dabrafenib dose(s) when administered in combination with the recommended trametinib dose for chronic continuous daily dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures (trough concentration) to the recommended adult dose
- To assess any preliminary anti-tumor activity of trametinib in combination with dabrafenib |
|
| 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) for study participation including pharmacokinetics sampling 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. Part C and Part D subjects between 12 months and < 18 years of age, inclusive
4. Part A subjects < 2 years of age will not be included in the initial dose escalation
5. Must have a disease that is relapsed/refractory to all potentially curative standard treatment regimens or must have a current disease for which there is no known curative therapy, or therapy proven to prolong survival with an acceptable quality of life.
6. Prior therapy: The subject’s disease (i.e. cancer, NF-1 with PN, or LCH) must have relapsed after or failed to respond to frontline curative therapy or there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. Subjects must have recovered to grade ≤1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment.
7. Performance score of ≥50% according to the Karnofsky / Lansky performance status scale.
8. Females of child-bearing potential must be willing to practice acceptable methods of birth control. Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prior to start of study drugs;
9. In France, subjects will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
10.10. Must have adequate multi organ function as defined by the following
values: renal function - 24 hr creatinine clearance (revised Schwartz
formula), or radioisotope glomerular filtration rate (GFR) >=60 milliliter
(mL) per minute per 1.73 meter square (mL/min/1.73m^2); or a serum
creatinine <=upper limit of normal (ULN) for age and gender; liver
functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN
for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes
of enrollment and toxicity monitoring the ULN for ALT will be 45 unit per
liter (U/L); cardiac function - corrected QT (QTcB) interval <480
milliseconds (msec), left ventricular ejection fraction (LVEF) >=lower
limit of normal (LLN) by ECHO.
•Able to swallow and retain enterally (per oral [PO] or nasogastric or
gastric tube) administered medication and does not have any clinically
significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels.
•Adequate Blood Pressure Control defined as: Blood pressure <= the
95th percentile for age, height, and gender.
Other protocol-defined inclusion criteria, including some for each part,
may apply |
|
| E.4 | Principal exclusion criteria |
1. Lactating or pregnant female.
2. History of another malignancy including resected non-melanomatous skin cancer
3. Subjects with Neurofibromatosis Type-1 (NF-1) associated optic pathway tumors are excluded if they are actively receiving therapy for the optic pathway tumor or do not meet criteria for Plexiform Neurofibroma or malignant solid tumor
4. Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya)
5. Subjects with NF-1 actively receiving therapy for the optic pathway tumour
6. Subjects with NF-1 and only Plexiform Neurofibroma (PN) lesions that cannot be evaluated by volumetric analysis
7. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures
8. Any prohibited medication(s) as described in Section 9.2.
9. Any medications for treatment of left ventricular systolic dysfunction
10. Part B cohorts 1, 2 and 3: Previous treatment with dabrafenib, trametinib or another MEK inhibitor (exception: prior treatment with sorafenib is permitted).
Patients who have had prior dabrafenib therapy may enroll into cohort B4.
Patients who have had prior dabrafenib therapy and had benefit from that therapy as determined by the investigator, are allowed in Part C or Part D
11. Administration of an investigational study treatment within 30 days preceding the first dose of study treatment(s) in this study
12. Have a known hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment or excipients that contraindicate their participation
13. Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, or liver metastases)
14. History of hepatic sinusoid obstructive syndrome (Venoocculsive disease) within the prior 3 months
15. History of heparin-induced thrombocytopenia
16. History of interstitial lung disease or pneumonitis
17. History or current evidence of retinal vein occlusion (RVO)
18. For subjects with solid tumors that are not primary central nervous system (CNS) tumors or NF-1 associated plexiform neurofibromas, subjects with symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression are excluded
19. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
20. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events Grade 2 or higher from previous anti-cancer therapy, except alopecia
21. 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 Medical Lead for guidance to enrol the subject
22. A history or evidence of cardiovascular risk including: a QT interval
corrected for heart rate using the Bazett's formula (QTcB) >=480 msec;
a history or evidence of current clinically significant uncontrolled
arrhythmias (clarification: Subjects with atrial fibrillation controlled for
>30 days prior to dosing are eligible); a history of acute coronary
syndromes (including myocardial infarction or unstable angina),
coronary angioplasty, or stenting within 6 months prior to
randomization; a history or evidence of current >=Class II congestive
heart failure as defined by the New York Heart Association (NYHA)
guidelines; subjects with intra-cardiac defibrillators; 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. Subjects with prosthetic valves can be
considered eligible provided they meet the criteria as stated above;
Treatment refractory hypertension defined as a blood pressure of
systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg
(or above 95th age-specific percentile listed in protocol), which cannot
be controlled by anti-hypertensive therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Safety Assessment of trametinib as assessed by Adverse Events (AEs)
2.Safety Assessment of trametinib as assessed by electrocardiogram
(ECG). Single 12-lead ECGs will be obtained to assess safety
3.Safety Assessment of trametinib as assessed by echocardiogram
(ECHO) ECHOs will be performed to assess cardiac ejection fraction and
cardiac valve morphology
4.Safety Assessment of trametinib as assessed by changes in laboratory
values. Laboratory assessments will include Hematology, Clinical
Chemistry, Routine Urinalysis and Other screening tests
5.Safety Assessment of trametinib assessed by changes in vital signs
Vital sign measurements will include systolic and diastolic blood
pressure, temperature, respiration rate and pulse rate
6.To determine the dose of trametinib that achieves similar exposures
(Ctau) to the recommended adult dose |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-5. From screening up to 63 months .
6. Days 15 and 22 |
|
| E.5.2 | Secondary end point(s) |
1.PK Assessment of trametinib parameters including Ctau (trough
concentration), area under the concentration-time curve over a period of
time (AUC [0-t]), area under the concentration-time curve over the
dosing interval (AUC [0-tau]), apparent clearance following oral dosing
(CL/F), maximum observed concentration (Cmax), Time of occurrence of
Cmax (tmax) and half-life (t1/2) of trametinib.
2.Safety and tolerability assessments for trametinib for AEs
3.Safety and tolerability assessments for trametinib for ECG.
12-lead ECGs will be performed to assess safety and tolerability
4.Safety and tolerability assessments for trametinib for changes in
laboratory values. Laboratory parameter including chemistry and
hematology
5.Safety and tolerability assessments for trametinib for vital signs.
Vital sign measurements will include systolic and diastolic blood
pressure, temperature, respiration rate and pulse rate
6.Tumor response for trametinib. Disease assessments will be conducted
and utilize disease specific response criteria (e.g. RECIST, RANO)
7.Effect of age and weight on the PK of trametinib. PK parameter will
include CL/F, volume of distribution (V/F), absorption rate (ka), and
coefficients for significant covariates
8.PK assessment of trametinib and dabrafenib when administered in
combination. PK parameters include Ctau, AUC (0-t), AUC (0-tau), CL/F,
Cmax, tmax, and Cavg
9.Palatability of trametinib and/or dabrafenib in pediatric subjects
assessed by palatability questionnaire.
To be completed after the first dose of study drug and no later than Day
8 (+/-3 days). Subjects will complete a form to evaluate the various
properties of the suspension (e.g., bitterness, sweetness, appearance,
texture and overall taste).
10.Safety Assessment of trametinib and dabrafenib when administered
in combination as assessed by Adverse Events (AEs)
11.Safety Assessment of trametinib and dabrafenib when administered
in combination as assessed by ECGs. 12-lead ECGs will be performed to
assess safety and tolerability
12.Safety Assessment of trametinib and dabrafenib when administered
in combination as assessed by Echo.
13.Safety Assessment of trametinib and dabrafenib when administered
in combination as assessed by changes in laboratory values. Laboratory
parameter including chemistry, hematology and urinalysis.
14.Safety Assessment of trametinib and dabrafenib when administered
in combination as assessed by changes in vital sign values. Vital sign
measurements will include systolic and diastolic blood pressure,
temperature, respiration rate and pulse rate
15.Safe and tolerable doses of dabrafenib when administered with
trametinib for chronic continuous daily dosing in pediatric subjects as
assessed by AEs.
16.Safe and tolerable doses of dabrafenib when administered with
trametinib for chronic continuous daily dosing in pediatric subjects as
assessed by ECGs. 12-lead ECGs will be performed to assess safety and
tolerability
17.Safe and tolerable doses of dabrafenib when administered with
trametinib for chronic continuous daily dosing in pediatric subjects as
assessed by Echo.
18.Safe and tolerable doses of dabrafenib when administered with
trametinib for chronic continuous daily dosing in pediatric subjects as
assessed by changes in lab values. Laboratory parameter including
chemistry, hematology and urinalysis.
19.Safe and tolerable doses of dabrafenib when administered with
trametinib for chronic continuous daily dosing in pediatric subjects as
assessed by changes in vital sings.
Vital sign measurements will include systolic and diastolic blood
pressure, temperature, respiration rate and pulse rate.
20.Safe and tolerable doses of dabrafenib when administered with
trametinib for chronic continuous daily dosing in pediatric subjects as
assessed by steady state Ctau of trametinib and by steady state AUC (0-
12) of dabrafenib
21.Tumor response for trametinib in combination with dabrafenib.
Disease assessments will be conducted and utilize disease specific
response criteria (e.g. RECIST, RANO) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 15 and Day 22
2-6. From screening up to 63 months
7. Day 15 and Day 22
8. Day 1, Day 15 and Day 22 of Part C and Part D
9. Day 8
10-19. From screening up to 63 months
20. Day 15 and Day 22 of Part C and Part D
21. From screening up to 63 months |
|
| 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 | 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 | 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 |
|
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Trametinib in Combination with Dabrafenib |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 4 |
| 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 |
| France |
| United Kingdom |
| United States |
|
| 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.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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