E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric Gastro Intestinal Stromal Tumor (GIST) |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | LLT |
E.1.2 | Classification code | 10062427 |
E.1.2 | Term | Gastrointestinal stromal tumor |
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 characterize the plasma PK profile of sunitinib and its active metabolite SU012662 in children and young adults with advanced GIST. |
|
E.2.2 | Secondary objectives of the trial |
• To investigate whether doses greater than the established pediatric MTD are tolerated in pediatric patients with GIST;
• To investigate the safety and tolerability of sunitinib in children and young adults with GIST;
• To investigate the anti tumor activity of sunitinib in children and young adults with GIST;
• To explore PK pharmacodynamic relationships with respect to safety and efficacy in children and young adults with GIST. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Histological diagnosis of GIST (refer to Section 6.1 of the protocol);
2. Tumor tissue must be available to assess KIT, PDGFRA, and BRAF
genotypes (for any of these genes where genotyping was not previously
performed) and to assess succinate dehydrogenase (SDH) protein
expression by immunohistochemistry. For exceptions see Section 6.1 of
the protocol;
3. Patients must have demonstrated disease progression or intolerance
to imatinib mesylate; have GIST with non-mutant KIT (tumor genotyping
may be performed prior to or during screening; patients with an
indeterminate KIT genotype are eligible if genotyping performed during
screening); or cannot obtain imatinib in their country;
4. Age 6 to <21 years;
5. Advanced, unresectable GIST for which there are no available options
for treatment with curative intent as assessed by the investigator;
6. Measurable (per Response Evaluation Criteria in Solid Tumors;RECIST version 1.1; or evaluable disease (Refer to Appendix 4 of the
protocol);
7. Resolution of all acute toxic effects of prior cancer treatment,
radiotherapy or surgical procedure to NCI CTCAE v4.0 grade ≤1;
8. ECOG Performance Status 0 2 (for patients ≥11 years of age) or
Lansky ≥50% (for patients <11 years);
9. Adequate organ function determined within 14 days prior to
enrollment, defined by:
• Peripheral absolute neutrophil count (ANC) ≥1500/μL;
• Platelet count ≥100,000/μL;
• Hemoglobin ≥10 g/dL;
• Total bilirubin ≤1.5 x upper limit of normal (ULN) for age;
• ALT (SGPT) or AST (SGOT) ≤ 3 x ULN for age;
• Serum albumin ≥2.0 g/dL;
• Serum amylase and lipase <1.5 x ULN;
• Serum creatinine based on age/gender;
• Blood Pressure (BP) < the 95th percentile for age, height and gender
(refer to Appendix 3 of the protocol for pediatric ranges);
• Cardiac shortening fraction or ejection fraction greater than the lower
limit of normal (LLN).
10. Evidence of a personally signed and dated informed consent (and
where applicable, assent) document indicating that the patient (or a
legal representative) has been informed of all pertinent aspects of the
study;
11. Patients (including legal guardian for minors where applicable) who
are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures, including anticipated
ability to swallow capsules;
12. Male and female patients of childbearing potential who are sexually
active must agree to use a highly effective method of contraception
throughout the study and for 30 days after the last sunitinib treatment.
A patient is of childbearing potential if, in the opinion of the investigator,
he/she is biologically capable of having children and is sexually active
(refer to section 4.3 of the protocol). |
|
E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the
study:
1. Current treatment with another investigational agent and/or systemic
anti-cancer therapy within 4 weeks before starting sunitinib treatment;
2. Prior sunitinib treatment;
3. Prior therapy with known risk for cardiovascular complications, eg,
high intensity anthracycline therapy (ie, total equivalent cumulative
dose > 100 mg/m2 of doxorubicin) or prior radiation therapy that
included the heart (cardiac silhouette) and/or craniospinal radiation;
4. Concomitant treatment with any drug having proarrhythmic potential
(terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol,
bepridil, haloperidol, risperidone, indapamide and flecainide);
5. Prior diagnosis of cardiac disease, including, but not limited to:
• Ongoing cardiac dysrhythmias of NCI CTCAE v4.0 ≥ grade 2, atrial
fibrillation of any grade;
• QTc interval >450 msec for males or >470 msec for females;
• Hypertension that cannot be controlled by medications;
• Any of the following within the 12 months prior to starting study
treatment: congestive heart failure, cerebrovascular accident including
transient ischemic attack or pulmonary embolism.
6. Grade ≥3 hemorrhage within 4 weeks prior to study entry;
7. Current treatment with therapeutic doses of coumarin derivative
anticoagulants such as warfarin or anti vitamin K agents;
8. Concurrent administration of strong cytochrome P450 3A (CYP3A4)
inhibitor(s) and/or inducer(s) within 7 and 12 days prior to first dose of
study drug, respectively (see Section 5.5.2 of the protocol);
9. Prior radiation to >25% of the bone marrow.
10. Patients with history of allergic reaction attributed to any component
of sunitinib capsules;
11. Pregnant females; breastfeeding females; males and females of
childbearing potential not using highly effective contraception or not
agreeing to continue highly effective contraception for 30 days after last
dose of investigational product; in the UK, males and females of
childbearing potential not using two (2) methods of highly effective
contraception or not agreeing to continue two (2) methods of highly
effective contraception for 30 days after last dose of investigational
product;
12. Active infection with HIV, or receiving antiretroviral therapy for HIV
disease;
13. Patients who are investigational site staff members or relatives of
those site staff members or patients who are Pfizer employees directly
involved in the conduct of the trial;
14. Other severe acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study
participation or investigational product administration or may interfere
with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for entry into this
study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetic parameters of sunitinib and its main active metabolite (SU012662) including total plasma exposure (AUC24) and oral clearance (CL/F). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Descriptive statistics for observed and dose-corrected (where appropriate) PK data will be reported for all patients with at least one PK observation by presenting the population size, arithmetic mean, standard deviation, percent coefficient of variation (CV%), median, minimum, maximum values at the end of the study. |
|
E.5.2 | Secondary end point(s) |
• Type, incidence, severity (graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0 [v4.0]), timing, seriousness, and relatedness of adverse events and laboratory abnormalities;
• Objective response rate, duration of response, PFS and OS at 2 years after study enrollment;
• Pharmacokinetic pharmacodynamic relationships with respect to safety and efficacy in pediatric GIST |
|
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 | 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 | 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 |
PK profile of sunitinib and its active metabolite SU012662 in children and young adults with GIST |
|
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
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 |
Argentina |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Czech Republic |
Egypt |
France |
Germany |
Hungary |
India |
Italy |
Mexico |
Netherlands |
Norway |
Poland |
Slovakia |
Spain |
Turkey |
United Kingdom |
United States |
Jordan |
|
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
|
End of Trial in all participating countries is defined as collection of the final data point in the study. Because this clinical trial includes a survival endpoint, the last data point is anticipated to be the last survival follow-up (i.e., date last known alive or of death) prior to the cutoff date for database lock for the final Clinical Study Report. |
|
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 | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |