Safety and efficacy objectives:The objective is to compare the safety and efficacy of masitinib at 6 of 7.5 mg/kg/day to imatinib at 400 or 600 mg, in patients with gastro-intestinal stromal tumour in first line medical treatment.
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
• Progression Free Survival (PFS)
Secondary outcome
Secondary endpoints:
• Tumour assessment:
-Overall Survival (OS)
-Time to progression (TTP)
-Objective response rate (CR + PR) at Week 12, Week 24 then every 24 weeks
Control disease rate (CR + PR + SO) at Week 12, Week 24 then every 24 weeks
Best response during study • Association between PFS, as, TTP, objective
response, control disease and the phenotype of mutations on KIT/POGF • Quality
of life assessment: Quality of Life according to the EORTC QLQ-C30
questionnaire at baseline and every 12 weeks until final visit ECOG Performance
Status at baseline and every 12 weeks until final visit • Safety profile using
the NCI CTC v4.0 classification
Background summary
1.4 Rationale for the development of masitinib in GIST
1.4.1 Comparative in vitro study of masitinib, imatinib and sunitinib activity
on c-kit activating mutations identified in GIST
GIST is the most common subtype of gastrointestinal (GI) tract sarcomas, which
also include leimyosarcomas, liposarcomas and other more rare histoloqical
subtypes. GISTs have been reported to represent about 3% of all malignant GI
tumours. These tumours are mostly due to c-Kit-activating mutations and rarely
to PDGFRa-activating mutations (3%). Activating c-Kit mutations occur in 70 to
80% of cases. The majority (70%) of these mutations are in-frame-deletions and
mis-sense mutations clustering in the 5'-end of the c-Kit juxtamembrane domain
(JMD exon 11) which causes ligand independent activation of the receptor. One
of the most representative JMD exon 11 mutations is the V5590 substitution.
Mutations in the extracellular domain of c-Kit (exon 9) are present in about 10
% of GIST, in which the Ala502-Tyr503 duplication is the most frequent
mutation. Functional consequences for exon 9-mutated receptors are the same
than exon 11mutated
receptors. Their signaling consequences, clinical correlation and response to
tyrosine kinase inhibitors are under intense investigation. Indeed, exon 11
mutants are highly sensitive to imatinib (Novartis), whereas GIST with exon 9
mutations failed to respond to this tyrosine kinase inhibitor (TKI). Because
partial or lack of response or imatinib intolerance have been observed in GIST
patients, it becomes important to develop new TKls. Masitinib (AB Science) and
sunitinib (Pfizer) are two of them.
Masitinib has been shown more efficient than imatinib in all the cell models
tested.
1.4.2 AB1010 is able to overcome imatinib resistance in cell assay
Cell lines sensitive to tyrosine kinase inhibitors can be rendered resistant in
vitro by exposing the cells to low concentrations of inhibitor, followed by
exposure to progressively increased concentrations. Resistance to imatinib
mesylate has been induced in cell lines that were initially sensitive to 1 µM.
Resistance to AB1010 has been induced in cell lines that were initially
sensitive to 0.2 µM. These observations suggest that it is critical to use high
initial concentrations (above IC50) of kinase inhibitor to avoid the induction
of resistance.
1.5 Overall conclusions
The toxicity profile of masitinib is acceptable and similar to imatinib.
Efficacy of masitinib shows a superiority trend over imatinib on PFS and
overall survival. These results are encouraging and support the initiation of a
comparative phase III study -to compare the efficacy and safety of AB1010 over
imatinib and in particular, test the non-inferiority/superiority efficacy
(superior PFS at month 24) and similar safety of masitinib over imatinib.
Study objective
Safety and efficacy objectives:
The objective is to compare the safety and efficacy of masitinib at 6 of 7.5
mg/kg/day to imatinib at 400 or 600 mg, in patients with gastro-intestinal
stromal tumour in first line medical treatment.
Study design
This is a prospective, multicenter, randomized, open-label, active-controlled,
non-inferiority, phase III study to compare efficacy and safety of masitinib to
imatinib at 400 or 600 mg in treatment of patients with gastro-intestinal
stromal tumour in first line medical treatment.
Intervention
NA
Study burden and risks
not applicable.
AB Science; 3, avenue George V
75008 Paris 75008
FR
AB Science; 3, avenue George V
75008 Paris 75008
FR
Listed location countries
Age
Inclusion criteria
1. Histologically proven, metastatic or locally advanced non resectable, or recurrent post surgery GIST
2. Naïve patient or patient previously treated with imatinib as neoadjuvant/adjuvant who relapsed after
imatinib discontinuation
3. Measurable tumour lesions with longest diameter >= 20 mm using conventional techniques or >= 10 mm with
spiral CT scan according RECIST criteria
4. C-Kit (CD117) positive tumours detected by immuno-histochemically or PDGFR positive if c-kit negative
5. ECOG < 1
6. Patient with adequate organ function:
Exclusion criteria
1. Patient previously treated by tyrosine kinase inhibitors except imatinib in case of inclusion criteria 2
2. Patient treated for a cancer other than GIST within 5 years before enrolment, with the exception of basal cell carcinoma or cervical cancer in situ
3. Patient with active central nervous system (CNS) metastasis or with history of CNS metastasis
4. Patient presenting with cardiac disorders defined by at least one of the following conditions:· Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)· Patient with cardiac failure class III or IV of the NYHA classification· Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)· Syncope without known aetiology within 3 months· Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension
5. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent
6. Patient with any condition that the physician judges could be detrimental to subjects participating in this study, including any clinically important deviations from normal clinical laboratory values or concurrent medical events
Previous treatment
7. Treatment with any investigational agent within 4 weeks prior baseline
8. Treatment by imatinib as neoadjuvant/adjuvant therapy within 4 weeks prior baseline
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 | EUCTR2008-000973-40-NL |
| ClinicalTrials.gov | NCT00812240 |
| CCMO | NL34450.078.10 |