| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced, metastatic or unresectable gastro-intestinal stromal tumour (GIST). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastrointestinal stromal tumours (GISTs) are rare cancers. GISTs belong to a group of cancers called soft tissue sarcomas. Sarcomas are cancers that develop in the supporting or connective tissues. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| 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 |
The objective of this study is to compare the safety and effectiveness of masitinib to imatinib in patients with metastatic or locally advanced gastro-intestinal stromal tumour (GIST) in first line medical treatment, primarily by assessing the progression-free survival of these patients.
Primary endpoint:
· Overall Progression Free Survival (PFS) according to central review |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to demonstrate further efficacy parameters as well as to evaluate the safety of masitinib.
The secondary endpoints include:
Assessment of the overall survival of patients.
Measurement of the time to progression of the disease.
Evaluation of the objective response rate (complete remission and partial remission) at week 12, week 24 and then every 24 weeks.
Measurement of the control disease rate (complete remission, partial remission and stable disease) at week 12, week 24 and then every 24 weeks.
Assessment of the best response during the study.
Evaluation of the association between progression-free survival, overall survival, time to progression, objective response, control disease and the phenotype of mutations on KIT/PDGF genes.
Assessment of the patient’s quality of life, according to the EORTC QLQ-C30 questionnaire and ECOG performance status at baseline and every 12 weeks until the final visit.
Assessment of the safety profile using the NCI |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 to RECIST criteria
4. C-Kit (CD117) positive tumours detected immuno-histochemically or PDGFR positive if c-Kit negative
5. ECOG ≤ 1
6. Patient with adequate organ function:
- absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L
- Haemoglobin ≥ 10 g/dL
- platelets (PTL) ≥ 75 x 10e9/L
- AST and ALT ≤ 3x ULN (≤ 5 x ULN in case of liver metastases)
- Gamma GT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases)Bilirubin ≤ 1.5x ULN (≤ 3 x ULN in case of liver metastases)
- Normal Creatinine or if abnormal Creatinine, Creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula)
- albumin > 1 x LLN
- proteinuria < 30 mg/dL on the dipstick; if proteinuria ≥ 30 mg/dL, 24 hours proteinuria ≤ 1.5g/24 hours
7. Patient with life expectancy > 6 months
8. Men or women, age >18 years
9. Contraception:
- Female patient of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agrees to use a highly effective method of contraception and an acceptable method of contraception by her male partner during the study and for 3 months after the last treatment intake.
- Male patient with a female partner of childbearing potential who agrees to use a highly effective method of contraception and an acceptable method of contraception by his female partner during the study and for 3 months after the last treatment intake or who agrees to use an acceptable method of contraception and a highly effective method of contraception by his female partner during the study and for 3 months after the last treatment intake.
Highly effective methods of contraception include:
- Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
- Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomized male (azoospermia assessed medically)
- Sexual abstinence (Its reliability should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
Acceptable methods of contraception include:
- Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
- Male or female condom with or without spermicide
- Cap, diaphragm, or sponge with spermicide
10. Patient should be able and willing to comply with study procedures as per protocol.
11. Patient should be able to understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures.
12. Patient able to, understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity.
13. Patient weight > 40 kg and BMI > 18 kg/m² |
|
| E.4 | Principal 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome of this study is the Progression Free Survival (PFS).
PFS is defined as the time from randomisation to first documentation of objective tumour progression (date of tumour assessment documenting progressive disease) or to death due to any cause. Any dose escalation will be considered as progression at the day of the dose escalation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Data base lock will be triggered after the required number of events has been reached. |
|
| E.5.2 | Secondary end point(s) |
- Tumour assessment:
· Overall PFS according to local review
· PFS rate every 12 weeks according to central review and local review
· Overall Survival (OS)
· Survival rate every 12 weeks
· Overall Time to progression (TTP)
· TTP rate every 12 weeks according to central review and local review
· Overall Time to Treatment Failure (TTF)
· TTF rate every 12 weeks
· Response rate (CR + PR) disease control rate (CR + PR + SD) every 12 weeks
· Best response
· Association between PFS, OS, TTP, TTF, response and the phenotype of mutations on KIT/PDGFR
- Quality of life assessment:
· Quality of Life according to the EORTC QLQ-C30 questionnaire every 12 weeks
· ECOG Performance Status every 12 weeks
- Safety
· Safety profile using the NCI CTC v4.0 classification |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Data base lock will be triggered after the required number of events has been reached. |
|
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | No |
| 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 | No |
| 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
|
| Patient will be treated until disease progression. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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