E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic or unresectable gastrointestinal stromal tumor |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062427 |
E.1.2 | Term | Gastrointestinal stromal tumor |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of Nilotinib in patients with unresectable or metastatic gastrointestinal stromal tumors. Efficacy is defined as the proportion of patients showing stable disease (SD), partial response (PR) or complete response (CR) during the first 6 months according to RECIST criteria. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the objective tumor response rate based on RECIST criteria (complete response (CR) and partial response PR) •To evaluate time to overall response (PR or CR) •To evaluate duration of response •To evaluate progression free survival (PFS) during the first 6 months using RECIST criteria •To evaluate overall survival (OS) •To evaluate the safety and tolerability of Nilotinib as measured by rate and severity of adverse events •To evaluate the population pharmacokinetics of Nilotinib •To compare RECIST and Choi criteria for response and time-to-event variables |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Age ≥18 years •Histologically confirmed diagnosis of GIST that is unresectable and/or metastatic and therefore not amenable to surgery or combined modality with curative intent prior to or at Visit 1 •At least one measurable site of disease on CT/MRI scan at Visit 1, as defined by RECIST criteria (see Post Text Suppl 3 for details) The scans should be at maximum 2 weeks old. New scans are only required as baseline scans if they are older then approx. 2 weeks. •WHO Performance Status of 0, 1 or 2 •Patients must have the following laboratory values (≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication.): 1.Potassium ≥ LLN, 2.Magnesium ≥ LLN, 3.Phosphorus ≥ LLN, 4.Total calcium (corrected for serum albumin) ≥ LLN •Patients must have normal organ, electrolyte, and marrow function as defined below: 1.Absolute Neutrophil Count (ANC) ≥ 1.5x 109/L; 2.Platelets ≥ 100 x 109/L; 3.ALT and AST ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if considered due to tumor; 4.Alkaline phosphatase ≤ 2.5 x ULN unless considered due to tumor; 5.Serum bilirubin ≤ 1.5 x ULN; 6.Serum lipase and amylase ≤ 1.5 x ULN; 7.Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min. (calculated creatinine clearance using Cockroft formula is acceptable) |
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E.4 | Principal exclusion criteria |
•Prior treatment with nilotinib •Treatment with any cytotoxic and/or investigational cytotoxic drug ≤ 4 weeks (6 weeks for nitrosurea or mitomycin C) prior to Visit 1 with the exception of imatinib targeted therapy as an adjuvant therapy •Prior or concomitant malignancies requiring active treatment other than GIST with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ •Impaired cardiac function at including any one of the following: 1.LVEF < 45% or below the institutional LLN range (whichever is higher) as determined by echocardiogram at Visit 1 2.Complete left bundle branch block 3.Use of a ventricular paced cardiac pacemaker 4.Congenital long QT syndrome or family history of long QT syndrome 5.History of or presence of significant ventricular or atrial tachyarrhythmias 6.Clinically significant resting bradycardia (< 50 beats per minute) 7.QTc > 450 msec on screening ECG (using the QTcF formula). If QTc > 450 msec and electrolytes are not within normal ranges (electrolytes should be corrected and then the patient rescreened for QTc. 8.Right bundle branch block plus left anterior hemiblock, bifascicular block 9.Myocardial infarction within 12 months prior to Visit 1 10.Other clinically significant heart disease (e.g., unstable angina, congestive heart failure or uncontrolled hypertension,) •Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol e.g. impairment of gastrointestinal (GI) function, or GI disease that may significantly alter the absorption of the study drugs, uncontrolled diabetes •Use of therapeutic coumarin derivatives (i.e. warfarin, acenoucumarol, phenprocoumon) •Use of any medications that prolong the QT interval and CYP3A4 inhibitors if the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug administration. Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents that prolong the QT interval as well as Post-Text Supplement 2. •Patients who have undergone major surgery ≤ 2 weeks prior to Visit 1 or who have not recovered from side effects of such surgery •Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation < 2 weeks prior to Visit 1 or who have not recovered from side effects of such therapy •A history of noncompliance to medical regimens or inability or unwillingness to return for scheduled visits •Patients who are pregnant, breast feeding or women of childbearing potential (WOCBP). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential Women of reproductive potential ,to include female partners of heterosexual or bisexual patients, must agree to use an effective method of contraception during the study and for up to three months following termination of the study. •Patients unwilling or unable to comply with the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary variable is defined as the best response at month 6 determined according to the RECIST criteria |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
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) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
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 | 3 |
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 |