| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with histologically confirmed unresectable or metastatic GIST, either who have not received prior therapy with TKIs or, who experienced recurrence of GIST > 6 months after stopping adjuvant treatment with imatinib. |
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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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare progression free survival (PFS) of nilotinib and imatinib when used as initial therapy of unresectable and/or metastatic GIST in patients either who have not received prior therapy with TKIs or who have recurrent GIST after stopping adjuvant treatment with imatinib. |
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| E.2.2 | Secondary objectives of the trial |
The first three objectives listed below are considered to be the key secondary objectives :
1. To compare the disease control rate (DCR, defined as the proportion of patients with a best overall response of complete response, partial response, or stable disease which lasted at least 24 weeks) of nilotinib and imatinib in the same patient population.
2. To compare the time to treatment failure (TTF) of nilotinib and imatinib.
3. To compare overall survival (OS) of nilotinib and imatinib.
4. To compare time to progression (TTP), response rate (RR), time to tumor response, and assess duration of response of nilotinib and imatinib (RECIST criteria).
5. To compare the safety and tolerability of nilotinib and imatinib.
6. To evaluate inter- and intra-patient variability in nilotinib and imatinib exposure over time, and to explore any relationship between the pharmacokinetic exposure of nilotinib or imatinib and clinical responses
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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 |
Extension study
Biomarker studies
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| E.3 | Principal inclusion criteria |
• Age ≥ 18 years
• At least one measurable site of disease on CT/MRI scan as defined by RECIST criteria (refer to Post-text supplement 2) based on investigator’s assessment
• Histologically confirmed diagnosis of GIST which is unresectable and/or metastatic and either:
o have not received prior therapy with imatinib or any investigational therapies (for example sunitinib or any other TKIs). Note: newly diagnosed patients may have received up to 14 days imatinib treatment for disease management while awaiting study start.
o have recurrent GIST ≥ 6 months after stopping adjuvant treatment with imatinib and have subsequently not received any other investigational therapies (for example sunitinib or any other TKIs).
For patients with recurrent GIST after stopping adjuvant imatinib two CT scans will be required prior to study entry: one demonstrating absence of disease following completion of adjuvant imatinib and another demonstrating recurrence of disease ≥ 6 months after discontinuation of adjuvant imatinib.
• WHO Performance Status of 0, 1 or 2
• Patients must have normal organ, electrolyte, and marrow function as defined below:
o Absolute Neutrophil Count (ANC) ≥ 1.5 x 10(9)/L
o Platelets ≥ 100 x 10(9)/L
o ALT and AST ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if considered due to tumor
o Alkaline phosphatase ≤ 2.5 x ULN unless considered due to tumor
o Serum bilirubin ≤ 1.5 x ULN
o Serum lipase and amylase ≤ 1.5 x ULN
o Serum potassium within the normal limits or corrected to within normal limits with supplements
o Total calcium (corrected for serum albumin) within the normal limits or corrected to within normal limits with supplements
o Serum magnesium within the normal limits or corrected to within normal limits with supplements
o Serum phosphorous within the normal limits or corrected to within normal limits with supplements
o Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min (calculated creatinine clearance using Cockroft formula is acceptable)
• A written informed consent must be obtained
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| E.4 | Principal exclusion criteria |
• Prior treatment with nilotinib or any other TKIs or targeted agents with the exception of adjuvant imatinib or, for patients with newly diagnosed metastatic/unresectable GIST whose disease requires therapy while awaiting study start, up to 14 days of treatment with imatinib (a washout period of 4 days will be required prior to the first dose of study medication).
• Patients who experience disease progression during adjuvant therapy with imatinib
• Prior or concomitant malignancies (except if the other primary malignancy is neither currently clinically significant or requiring active intervention) other than GIST with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ
• Impaired cardiac function, including any one of the following:
o LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by echocardiogram or MUGA scan.
o Inability to determine the QT interval on ECG.
o Complete left bundle branch block.
o Use of a ventricular-paced pacemaker.
o Congenital long QT syndrome or a known family history of long QT syndrome.
o History of or presence of clinically significant ventricular or atrial tachyarrhythmias.
o Clinically significant resting bradycardia (< 50 beats per minute).
o QTc > 450 msec (using the QTcF formula) as determined by central reading. If QTcF > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
o History or signs of prior myocardial infarction.
o History of unstable angina (during the last 12 months).
o Other clinically significant heart disease (e.g. 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. uncontrolled diabetes, active or uncontrolled infection.
• History of significant congenital or acquired bleeding disorder unrelated to cancer.
• Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery.
• History of non-compliance to medical regimens or inability to grant consent.
• Use of therapeutic coumarin derivatives
• Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug administration.
• Patients actively receiving therapy with strong CYP3A4 inhibitors (e.g, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
• Patients actively receiving therapy with strong CYP3A4 inducers (e.g, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John’s Wort) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
• History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
• Acute or chronic uncontrolled liver, or severe renal disease considered unrelated to disease.
• Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation < 2 weeks or who have not recovered from side effects of such therapy
• Women who are pregnant, breast feeding or adults of reproductive potential not employing an effective method of birth control. Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective method of contraception during the study and for up to three months following discontinuation from the study. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) |
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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 | No |
| 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 | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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