| 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 | 17.1 |
| 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 | No |
| 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 determine the acceptability and palatability of trametinib in
pediatric subjects |
|
| 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 2 years and < 18 years of age (inclusive) at the time of signing the informed consent form (Part C between 12 months and < 18 years of age, inclusive).
3. Must have a disease that is relapsed/refractory to all potentially curative standard treatment regimens or have a disease for which there are no standard treatment regimens that are potentially curative.
4. Prior therapy: The subject’s cancer (not NF-1 with PN) 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. All subjects (including NF-1 with PN) must have recovered to grade ≤1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment.
5. Performance score of ≥50% according to the Karnofsky/Lansky performance status scale.
6. Females of child-bearing potential must be willing to practice acceptable methods of birth control (see Section 10.1 of protocol). Additionally, females of childbearing potential must have a negative serum pregnancy test within 14 days prior to enrollment, throughout treatment period and for 4 months after last dose of study drug.
7. Must have adequate organ function as defined by the following values:
- Renal function: 24 hr creatinine clearance (revised Schwartz formula), or radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2; or a serum creatinine ≤ ULN for age and gender as defined in the table on page 73 of the protocol.
- Liver function defined as:
a. Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x ULN for age
b. ALT <2.5 x ULN; for the purposes of enrollment and toxicity monitoring the ULN for ALT will be 45 U/L.
- Cardiac function defined as:
a. Corrected QT (QTcB) interval <480 msec
b. LVEF ≥LLN by ECHO
8. Able to swallow and retain enterally (PO or nasogastric or gastric tube) administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as alabsorption syndrome or major resection of the stomach or bowels.
9. Adequate Blood Pressure Control defined as:
- Blood pressure ≤ the 95th percentile for age, height, and gender (Appendix 7 in protocol) measured as described in Section 3.13.3.1.
10. 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 |
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Lactating or pregnant female.
2. History of another malignancy including resected non-melanomatous skin cancer.
3. Subjects with 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 PN or malignant solid tumor (Subjects with NF-1 and isolated optic pathway tumors as only site of evaluable tumor are not eligible for enrollment).
4. Subjects with a history of NF-1 related cerebral vascular anomaly are excluded.
5. Subjects with NF-1 and active optic glioma are excluded.
6. Subjects with NF-1 and PN 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), currently used or expected to be required, as described in Section 9.2.
9. Any medications for treatment of left ventricular systolic dysfunction
10. Part B and Part C only: Previous treatment with dabrafenib (cohort B4), trametinib or another MEK inhibitor (exception: prior treatment with sorafenib is permitted)
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 immediate or delayed 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 sensitivity to heparin or heparin-induced thrombocytopenia.
16. History of interstitial lung disease or pneumonitis.
18. History or current evidence RVO or RPED
19. For subjects with solid tumors that are not primary CNS tumors, subjects with symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression are excluded.
NOTE: Subjects previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for >3 months, are asymptomatic and are not currently taking corticosteroids, or are on stable dose or decreasing of corticosteroids for at least 7 days prior to enrolment are permitted.
20. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.
21. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia.
22. 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 GlaxoSmithKline (GSK) medical monitor for guidance to enrol the subject.
23. A history or evidence of cardiovascular disease
- Part C only, Abnormal cardiac valve morphology (≥Grade 2) documented by echocardiogram. Subjects with moderate valvular thickening should not be entered on study; |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Adverse Events (AEs); ECG; ECHO; changes in laboratory values and vital signs. Steady state Ct (tau) of trametinib |
|
| 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 22 days of treatment. |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics: Ct (trough), AUC(0-t), AUC(0-tau), apparent clearance following oral dosing (CL/F) Cmax, tmax and t½ of trametinib, as appropriate.
Safety Endpoints: AEs; ECG; changes in laboratory values and vital signs
Tumor response as defined in the protocol
To determine the effect of covariates such as age and weight on the pharmacokinetics of trametinib using a population pharmacokinetics approach: CL/F, volume of distribution (V/F), absorption rate (ka), and coefficients for significant covariates
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety and efficacy endpoints will be evaluated throughout a subject’s participation in the study. Pharmacokinetic endpoints will be evaluated over the first 22 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 | 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) | 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 | 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 | 3 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
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