| 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 any prior anti-neoplastic therapy or, who experienced recurrence of GIST > 6 months after stopping adjuvant treatment with imatinib. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062427 |
| E.1.2 | Term | Gastrointestinal stromal tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 any prior anti-neoplastic therapy or who have recurrent GIST after stopping adjuvant treatment with imatinib. |
|
| 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
|
|
| 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 |
This study will consist of two parts: a core study followed by an extension study, in wich patients will be offered the alternative study treatment. After the final efficacy analysis, depending on the outcome, a decision may be taken to transfer all patients remaining on the core study to the extension study (without switching the treatment). Current protocol and related documents are also valid for the extension study (PTS 1).
Study Title: A randomized, open-label, multicenter phase III study to evaluate the efficacy and safety of nilotinib versus imatinib in adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) |
|
| 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:
•have not received any prior anti-neoplastic therapy other than adjuvant
imatinib. Note: newly diagnosed patients may have received up to 14
days of treatment with imatinib for disease management while awaiting
entry to the study
or
•had no clinical or radiological evidence of disease during the adjuvant
treatment with imatinib, have recurrent GIST ≥ 6 months after stopping
adjuvant treatment with imatinib, and who have subsequently not
received any other therapies,
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:
•Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
•Hemoglobin ≥ 9.0 g/dL
•Platelets ≥ 100 x 109/L
•ALT and AST ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if
considered due to liver metastases
•Alkaline phosphatase ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to
liver metastases
•Serum bilirubin ≤ 1.5 x ULN
•Serum lipase and amylase ≤ 1.5 x ULN
•Serum potassium within the normal limits or corrected to within normal
limits with supplements
•Total calcium (corrected for serum albumin) within the normal limits or
corrected to within normal limits with supplements
•Serum magnesium within the normal limits or corrected to within
normal limits with supplements
•Serum phosphorous within the normal limits or corrected to within
normal limits with supplements
•Serum creatinine ≤ 1.5 x ULN
•A written informed consent must be obtained |
|
| E.4 | Principal exclusion criteria |
•Any prior anti-neoplastic therapy (e.g. TKIs, chemotherapy, investigational therapy) with the exception of patients who have received adjuvant imatinib or patients with newly diagnosed
metastatic/unresectable GIST whose disease requires therapy while
awaiting entry to the study, up to 14 days of treatment with imatinib (a
washout period of a minimum of 4 days will be required prior to the first
dose of study medication).
•History of active malignancy (other than GIST) within 10 years prior to
study entry 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:
•LVEF < 45% or below the institutional lower limit of the normal range
(whichever is higher) as determined by echocardiogram or MUGA scan.
•Inability to determine the QT interval on ECG.
•Complete left bundle branch block.
•Use of a ventricular-paced pacemaker.
•Congenital long QT syndrome or a known family history of long QT
syndrome.
•History of or presence of clinically significant ventricular or atrial
tachyarrhythmias.
•Clinically significant resting bradycardia (< 50 beats per minute).
•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 rescreened
for QTc.
•History or signs of prior myocardial infarction (during the last 12
months).
•History of unstable angina (during the last 12 months).
•Other clinically significant heart disease (e.g. congestive heart failure
or uncontrolled hypertension).
•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.
•Known symptomatic brain metastases.
•Major surgery within 4 weeks prior to randomization or who have not
recovered from prior surgery.
•History of non-compliance to medical regimens or inability to grant
consent.
•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. Please see
torsades.org/medical-pros/drug-lists/printable-drug-list.cfm or
http://www.arizonacert.org/medical-pros/drug-lists/drug-lists for a list
of agents that prolong the QT interval. This list may not be
comprehensive.
•Patients actively receiving therapy with strong CYP3A4 inhibitors and
the treatment cannot be either discontinued or switched to a different
medication prior to starting study drug. See Post-text supplement 4 for a
list of these medications. This list may not be comprehensive.
•Patients actively receiving therapy with strong CYP3A4 inducers and
the treatment cannot be either discontinued or switched to a different
medication prior to starting study drug. See Post-text supplement 4 for a
list of these medications.. This list may not be comprehensive.
•Patients actively receiving therapy with herbal medicines that are
CYP3A4 inhibitors and/or inducers, and the treatment cannot be either
discontinued or switched to a different medication prior to starting study
drug. These herbal medicines may include Echinacea, (including E.
purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's
Wort, and Ginkgo.
•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),
except for gastrectomy.
•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 within 4 weeks or
limited field radiation for palliation within 2 weeks prior to
randomization or who have not recovered from side effects of such
therapy
•Women who are a) pregnant, b) breast feeding c) of childbearing
potential without a negative pregnancy test prior to baseline and (d)
female of childbearing potential unwilling to use contraceptive
precautions throughout the trial (post menopausal women must be
amenorrheic for at least 12 months to be considered of non-childbearing
potential.) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) |
|
| 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 | No |
| 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 | 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) | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 68 |
| 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 | 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
| |
| 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 | |
| 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 |
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