E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric Gastro Intestinal Stromal Tumor (GIST) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | LLT |
E.1.2 | Classification code | 10062427 |
E.1.2 | Term | Gastrointestinal stromal tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 (defined as unresectable without major morbidity, metastatic or recurrent) GIST. |
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E.2.2 | Secondary objectives of the trial |
• To investigate whether doses greater than the established pediatric MTD are tolerated in chemotherapy naive 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patient eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Histological diagnosis of GIST;
2. KIT genotype (consent for testing sufficient if previous disease progression/intolerance to imatinib);
3. Patients with KIT mutant GIST must have demonstrated either disease progression or intolerance to imatinib mesylate;
4. Age 6 - <21 years;
5. Unresectable without major morbidity, metastatic or recurrent GIST;
6. Measurable (per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1) or evaluable disease;
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) ≥1000/µL without growth factor support;
• Platelet count ≥100,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7 days prior to enrollment);
• Hemoglobin ≥10 g/dL;
• Total bilirubin ≤1.5 x upper limit of normal (ULN) for age;
• ALT (SGPT) ≤110 U/L;
• Serum albumin ≥2.0 g/dL;
• Serum amylase and lipase <1.5 x ULN;
• Serum creatinine based on age/gender as follows:
Age Maximum Serum Creatinine
(mg/dL)
Male Female
6 to <10 years 1 1
10 to <13 years 1.2 1.2
13 to <16 years 1.5 1.4
≥16 years 1.7 1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
• Blood Pressure (BP) < the 95th percentile for age, height and gender
• Cardiac shortening fraction or ejection fraction greater than the lower limit of normal (LLN) (institutional norm).
10. Evidence of a personally signed and dated informed consent (and where applicable, assent) document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study;
11. Patients (including legal guardian for minors) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
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 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
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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, prior radiation therapy that included the heart (cardiac silhouette) and/or craniospinal radiation;
Patients with prior anthracycline exposure may be included if the total cumulative exposure was ≤150mg/m2;
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 study entry, respectively;
9. Prior radiation to >25% of the bone marrow;
10. Patients with history of allergic reaction attributed to sunitinib or any component of sunitinib capsules;
11. Pregnant females; breastfeeding females; males and females of childbearing potential; 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; 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, 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. |
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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). |
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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. |
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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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 |
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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 | No |
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.8.3 |
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 |
Argentina |
Brazil |
Canada |
Chile |
Egypt |
Jordan |
Mexico |
Turkey |
United States |
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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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
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 |