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
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. |
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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 (ie, > or equal 1 malignant tumor mass that may be accurately measured in at least 1 dimension > or equal 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 > or equal 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 (eg, 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 < or equal 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]) < or equal 2.5 x upper limit of normal (ULN). If liver function abnormalities are due to underlying malignancy, then AST and ALT may be < or equal 5 x ULN • Total serum bilirubin < or equal 1.5 x ULN • Prothrombin time (PT) and partial thromboplastin time (PTT) < or equal 1.5 x ULN • Serum albumin > or equal 3.0 g/dL • Absolute neutrophil count (ANC) > or equal 1500/microliter • Platelets > or equal 100,000/microliter • Hemoglobin > or equal 9.0 g/dL • Serum creatinine < or equal 1.5 x ULN • Serum amylase or lipase < or equal 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. Pre existing thyroid abnormality of thyroid function that cannot be maintained in the normal range with medication. 10. Ongoing cardiac dysrhythmias of NCI CTCAE Grade > or equal 2, atrial fibrillation of any Grade, or prolongation of the QTc interval to >450 msec for males or >470 msec for females. 11. Left ventricular ejection fraction (LVEF) < or equal 50% as measured by either multigated acquisition (MUGA) scan or echocardiogram (ECHO). 12. Evidence of neurological signs/symptoms secondary to brain metastases, spinal cord compression, or new evidence of brain or leptomeningeal disease. 13. Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS) related illness. 14. 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. 15. 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. Observation time for calculating PFS will be censored on the date of the last tumor assessment on study 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 a 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. |
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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 | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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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see protocol, part 13.1 + 13.2 |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |