E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
TREATMENT OF PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS (GIST) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051066 |
E.1.2 | Term | Gastrointestinal stromal tumour |
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 | 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. |
|
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 |
|
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 |
|
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/L •Hemoglobin >9.0 g/dL •Serum creatinine <1.5 x ULN •Serum amylase and 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. |
|
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. |
|
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. |
|
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 | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
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 |
|
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 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) |
|
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |