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…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy variable is progression free survival.
Secondary outcome
The key secondary efficacy variables include disease control rate (DCR), time
to treatment failure (TTF) and overall survival (OS).
Background summary
Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms that are
thought to arise from the interstitial cells of Cajal or their mesenchymal stem
cell precursor.
The management of GIST has evolved very rapidly since its molecular
pathogenesis was identified. GISTs are poorly responsive to chemotherapy (<10%
response rates) and the role of radiotherapy in their management is limited.
Surgery is the first-line therapy for resectable, non-metastatic GIST. However,
the majority of patients eventually develop recurrence or metastatic disease
(40-90%).
Imatinib is the first-line therapy for metastatic GIST.
For patients whose disease has progressed during, or who are intolerant to
imatinib therapy, sunitinib is the available second line treatment.
Unfortunately the benefit of such second-line therapy appears short with median
failure after only approximately 6 months. Furthermore, an unexpected high
percent of persistent, primary hypothyroidism in a series of 42 patients
treated with sunitinib (36%) was recently reported. Others have observed
cardiac events, most commonly congestive heart failure, in 11% of patients
(N=75 patients) with imatinib-resistant GIST treated with sunitinib for a
median of 33.6 weeks.
Thus, current available therapies may not be optimal for patients with
metastatic and/or unresectable GIST, and there is the potential for new
frontline agents with an improved safety and clinical benefit.
Nilotinib is a highly effective competitive inhibitor of the protein tyrosine
kinase activity of Bcr-Abl. In addition, nilotinib inhibits the tyrosine kinase
activity of KIT and PDGFR* which are associated with GISTs. Although nilotinib
and imatinib exhibit similar potencies against the KIT and PDGFR target
enzymes, they exhibit major differences in cell transport. These differences
can give rise to much higher intracellular levels of nilotinib, compared to
imatinib.
Study objective
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.
Study design
This is a randomized, open-label, multi-center, two-arm, Phase III study to
evaluate the efficacy and safety of nilotinib versus imatinib.
A total of 736 patients will be randomized 1:1 to receive either nilotinib or
imatinib (368 patients per arm).
This study will consist of two parts: a core study followed by an extension
study, in which patients will be offered the alternative study treatment.
Intervention
Replacement of standard therapy (imatinib) with nilotinib.
Study burden and risks
- every potential side effect of nilotinib and/or imatinib
- Physical examinations including vital signs, standard MRI / CT scans, ECG,
blood for PK assessment, regular monitoring of hematology (including
coagulation parameters), blood chemistry, serum/urine pregnancy.
Raapopseweg 1
6824 DP Arnhem
NL
Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
Age * 18 years
At least one measurable site of disease on CT/MRI scan as defined by RECIST criteria
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
- have 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.
WHO Performance Status of 0, 1 or 2
Patients must have normal organ, electrolyte, and marrow function
Exclusion criteria
Any prior anti-neoplastic therapy (eg. 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
Prior malignancies 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 re-screened 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 metastasis
Major surgery within 4 weeks prior to randomization or who have not recovered from prior surgery.
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 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 and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
Patients actively receiving therapy with herbal medicines that are CYP3A4 inhibitors and/or inducers, and 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), 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-004758-34-NL |
| Other | N/A |
| CCMO | NL26413.058.09 |