E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
TREATMENT OF PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS (GIST) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051066 |
E.1.2 | Term | Gastrointestinal stromal tumour |
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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 compare the progression-free survival (PFS) associated with sunitinib (37.5 mg daily) with that associated with imatinib 800 mg daily in subjects whose disease progressed on imatinib 400 mg daily. |
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E.2.2 | Secondary objectives of the trial |
•To compare the objective response rates (OR) between the two regimens •To assess time to tumor response (TTR) between the two regimens in responders •To compare duration of response (DR) between the two regimens in responders •To compare time to treatment failure (TTF) between the two regimens •To compare overall survival between the two regimens •To assess pain relief / pain progression in the two regimens •To assess patient-reported outcomes (PROs) •To evaluate safety and tolerability of the two drug regimens |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Lead-in safety Sub-study, Protocol A6181112, 19th May 2008 : A safety sub study will be conducted in one study centers. The purpose of the study will be to evaluate pharmacokinetics and treatment related adverse events in subjects taking a dose of sunitinib 24 hours after a last dose of imatinib. Six subjects will be entered and assessed as below. Subjects should be asked to take their last dose of imatinib in the morning on the day prior to coming to the clinic for the first dose of sunitinib. A dose of sunitinib (37.5 mg) will be administered in the clinic approximately 24 hours after the last dose of imatinib (400 mg). Single ECG will be performed for the measurement of QTc interval at screening and triplicate ECGs at day 1 approximately 6 hours post first dose of sunitinib. A corresponding blood sample should be collected at 6 hours post dose (after the ECG) for the measurement of plasma sunitinib and SU012662 concentrations. Triplicate ECG measurements will be performed prior to dosing at 7 and 14 days after the start of sunitinib treatment. Predose (trough) blood samples for measurement of sunitinib and SU012662 will also be taken at 7 and 14 days after the start of sunitinib treatment. Complete blood counts and blood chemistry will be performed at baseline; on Day 7 and on day 14 of treatment. All patients will be evaluated for adverse events. Seven days following the first dose, subjects will be assessed for any adverse reactions occurring during the first week of treatment. If 2 or more subjects out of the 6 present with a Grade 3 or 4 treatment related adverse event during the first week, an internal safety assessment committee will be convened and the safety data reviewed. Changes to the main protocol may be made after the convening of this committee. If there are no, or only one patient with a Grade 3 or 4 treatment related adverse reaction in the first week enrollment to the main study may begin and the sub study will proceed as below. Following the treatment of the first 6 subjects, an additional 6 subjects will be treated and assessed as above to add additional adverse event, ECG and PK data to the database in subjects taking a dose of sunitinib 24 hours after a 400 mg dose of imatinib. If 2 or more patients in the second cohort of 6 subjects experience a treatment related Grade 3 or 4 adverse event within the first week, the safety assessment committee will be convened and the safety data reviewed including data for any patients in the main study. Subjects participating in the lead in safety study must meet all inclusion/exclusion criteria for the main study including the avoidance of potent CYP3A4 inhibitors/inducers within 7 and 12 days, respectively, prior to the first study drug dose. No potent CYP3A4 inhibitors/inducers should be taken during the sub study period. Residual concentrations of imatinib at 24 hours are unlikely to be sufficient to cause an interaction with sunitinib. Based on previous experience with sunitinib, this sample size should provide an adequate number of subjects to evaluate this in order to provide evidence for tolerability sufficient to proceed to the main study. Subjects participating in the lead in safety sub study may proceed to the main study. They will be included in the analysis of safety in the main study, but not included in the analysis of efficacy.
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E.3 | Principal inclusion criteria |
1. Histopathologically-proven diagnosis of malignant GIST that is not amenable to surgery, radiation, or combined modality therapy with curative intent. 2. Evidence of unidimensionally measurable disease (i.e., ≥1 malignant tumor mass that may be accurately measured in at least 1 dimension ≥20 mm with conventional radiographic techniques or magnetic resonance imaging [MRI], or if spiral computerized tomography [CT] scan, twice the reconstruction interval used [lesion size ≥10-16 mm depending on interval]). Tumor evaluation by positron emission tomography (PET) scan or by ultrasound may not substitute for CT or MRI scans. Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions, and disease documented by indirect evidence only (e.g., by laboratory tests such as alkaline phosphatase) are not considered measurable. 3. Currently being treated with imatinib mesylate. Treatment with imatinib must be continued until randomization. 4. Must have experienced failure of prior treatment with imatinib mesylate 400 mg per day defined by progression of disease according to RECIST criteria during treatment. Radiographic evidence of disease progression on imatinib mesylate must be confirmed by the Investigator prior to enrollment in the study. 5. Male or female, 18 years of age or older. 6. ECOG performance status 0 or 1. 7. Resolution of all toxic effects of any prior imatinib mesylate therapy, surgical procedures, radiotherapy, or cryotherapy to NCI CTCAE (Version 3.0) grade 1 and to the baseline laboratory values as defined in inclusion criterion #8 8. Adequate organ function as defined by the following criteria: •Serum aspartate aminotransferase (AST; serum glutamate-oxalate transferase [SGOT]) and serum alanine aminotransferase (ALT; serum glutamate-pyruvate transferase [SGPT]) <2.5 x upper limit of normal (ULN). If liver function abnormalities are due to underlying malignancy, then AST and ALT may be <5 x ULN •Total serum bilirubin <1.5 x ULN •Prothrombin time (PT) and partial thromboplastin time (PTT) <1.5 x ULN •Serum albumin >3.0 g/dL •Absolute neutrophil count (ANC) >1500/L •Platelets >100,000/µL •Hemoglobin >9.0 g/dL •Serum creatinine <1.5 x ULN •Serum amylase or lipase <1.0 x ULN 9. Signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial prior to enrollment. 10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
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E.4 | Principal exclusion criteria |
1. Current treatment with any chemotherapy, chemoembolization therapy, immunotherapy, or investigational anticancer agent other than imatinib mesylate. 2. Treatment of subjects with imatinib mesylate-resistant disease with surgery, radiotherapy, and/or cryotherapy that affected all areas of measurable disease where progression on imatinib mesylate therapy had been demonstrated. 3. Having previously discontinued use of imatinib prior to randomization. 4. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri. 5. Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other thromboembolic event. 6. Treatment with potent CYP3A4 inhibitors and inducers within 7 and 12 days, respectively, prior to study drug administration. Potent CYP3A4 inhibitors and inducers will not be allowed as concomitant medications during the study. 7. Current treatment with therapeutic doses of anticoagulant (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed). 8. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy). 9. Ongoing cardiac dysrhythmias of NCI CTCAE grade 2, atrial fibrillation of any grade, or prolongation of the QTc interval to >450 msec for males or >470 msec for females. 10. Left ventricular ejection fraction (LVEF) ≤50% as measured by either multigated acquisition (MUGA) scan or echocardiogram (ECHO) 11. Evidence of neurological signs/symptoms secondary to brain metastases, spinal cord compression, or new evidence of brain or leptomeningeal disease. 12. Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness. 13. Pregnancy or breastfeeding. Subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) within the 7 days prior to enrollment. Male subjects must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate. 14. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug 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) |
The primary endpoint of the main study is progression free survival (PFS). Progression free survival is defined as the time from randomization to first progression of disease (PD) or death for any reason in the absence of documented PD. PFS data will be censored on the date of the last tumor assessment on study (28 days after the last dose of study medication) for subjects who do not have objective tumor progression and who do not die while on study. Subjects lacking an evaluation of tumor response after randomization will have their PFS time censored on the date of randomization with duration of 1 day. Subjects who start a new anti-cancer therapy without documented PD prior to start of this therapy will be censored at the date of the last tumor assessment prior to the start of the new therapy. The primary analysis of PFS will be performed in the ITT population. The log-rank test (two-sided) will be used to compare PFS time between the two arms, stratified by previous imatinib treatment status. |
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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 | Yes |
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 a MS of the EU is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the trial as stated in the regulatory application (i.e.CTA) and ethics application in the Member State.Poor recruitment (recruiting less than the anticipated number in the CTA) by a MS is not a reason for premature termination but is considered a normal conclusion to the trial in that MS. For more infomation please refer to the Clinical Protocol (Section n. 13) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
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 |