| Eligibility |
Inclusion Criteria:
1. Patients must provide written informed consent prior to performance of study-specific
procedures or assessments and must be willing to comply with treatment and follow-up.
Informed Consent must be obtained prior to start of the screening process. Procedures
conducted as part of the patient´s routine clinical management (e.g. blood count,
imaging tests, etc.) and obtained prior to signature of informed consent may be used
for screening or baseline purposes as long as these procedures are conducted as
specified in the protocol.
2. Male or female subjects =18 years of age
3. Histologically confirmed GIST KIT/PDGFR wild-type, unresectable or metastatic GIST
(confirmed by central laboratory). Paraffin-embedded tumor block must be provided by
all subjects during screening period.
4. Screening of mutations done in exon 11, 9, 13 and 17 in KIT gene and in 12 and 18
exons of PDGFR gene
5. Subjects must have at least one measurable lesion according to RECIST v1.1 criteria. A
lesion in a previously irradiated area is eligible to be considered as measurable
disease as long as there is objective evidence of progression of the lesion prior to
study enrolment.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
7. Adequate bone marrow, liver, and renal function as assessed by the following
laboratory requirements conducted within 7 days of starting study treatment:
- Total Bilirubin = 1.5 x the upper normal limit (UNL). Documented Gilbert Syndrome
is allowed if total bilirubin is mildly elevated (=6mg/dl).
- Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) = 3.0 x UNL
(=5xUNL for subjects with liver involvement of GIST)
- Lipase =1.5 x UNL
- Serum Creatinine = 1.5 x UNL
- Glomerular filtration rate (GFR) = 30ml/mn/1.73 m2 according to the Modified Diet
in Renal Disease (MDRD) abbreviated formula.
- International Normalized Ratio (INR) =1.5xUNL and partial thromboplastin time
(PTT) or activated partial thromboplastin time (aPTT) =1.5xUNL. Subjects who are
being treated with an anti-coagulant, such as warfarin or heparin, will be
allowed to participate provided that no prior evidence of an underlying
abnormality in these parameters exists. Close monitoring of at least weekly
evaluations will be performed until INR and PTT are stable based on a pre-dose
measurement as defined by the local standards of care.
- Platelet count =100000mm3, hemoglobin (Hb) = 9.0 g/dl, absolute neutrophil count
(ANC) =1500/mm3. Blood transfusions to meet the inclusion criteria will not be
allowed.
- Alkaline phosphatase limit = 2.5 x UNL (= 5x UNL for subjects with disease
involving the liver)
8. Women of childbearing potential and men must agree to use adequate contraception from
the moment of signing the Informed Consent Form until at least 3 months after the last
study drug administration. The investigator or a designated associate is requested to
advise the subject on how to achieve an adequate birth control. Adequate contraception
is defined in the study as any medically recommended method (or combination of
methods) as per standard of care.
9. Women of childbearing potential must have a blood or urine pregnancy test performed a
maximum of 7 days before start of study treatment, and a negative result must be
documented before start of study treatment.
Exclusion Criteria:
1. Prior systemic treatment for GIST BESIDES IMATINIB. Patients that have relapsed after
receiving imatinib during adjuvant setting and patients who are on treatment or have
been treated with Imatinib as first line of advanced KIT/PDGFRa wild type GIST are
eligible.
2. Cancer other than GIST within 5 years prior to randomization EXCEPT for curatively
treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder
tumors (Ta (Non Invasive tumor), and Tis (Carcinoma In situ)).
3. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
before the start of study medication.
4. Congestive Heart Failure New York Heart Association (NYHA) = class 2.
5. Unstable angina (angina symptoms at rest, new-onset angina, ie, within the lasts 3
months prior to entering study) or myocardial infarction (MI) within the past 6 months
before the start of study medication.
6. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are
permitted).
7. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure >
90mmHg despite optimal medical management).
8. Subjects with pheochromocytoma.
9. Arterial thrombotic or embolic events such as cerebrovascular accident (including
transient ischemic attacks), or pulmonary embolism within 6 months from start of study
treatment.
10. Venous thrombotic events such as deep vein thrombosis within the 3 months before the
start of study treatment.
11. Ongoing infection > grade 2 National Cancer Institute- Common Terminology Criteria for
Adverse Events (NCI-CTCAE) version 4.03
12. Known history of human immunodeficiency virus (HIV) infection.
13. Subjects with seizure disorder requiring medication
14. Symptomatic metastasis in brain or meningeal tumors.
15. History of organ allograft.
16. Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding
event = NCI-CTCAE version 4.03 grade 3 or higher within 4 weeks prior to start of
study treatment.
17. Non-healing wound, ulcer, or bone fracture.
18. Renal failure requiring hemo- or peritoneal dialysis.
19. Dehydration NCI-CTCAE version 4.03 grade = 1
20. Substance abuse or medical, psychological, or social conditions that may interfere
with the subject´s participation in the study or evaluation of the study results.
21. Known hypersensitivity to the study drug, study drug class, or excipients in the
formulation.
22. Any illness or medical conditions that are unstable or could jeopardize the safety of
the subject and his/her compliance in the study
23. Interstitial lung disease with ongoing signs and symptoms at the time of screening.
24. Subjects unable to swallow oral medication
25. Persistent proteinuria of NCI-CTCAE version 4.03 grade 3 or higher (>3.5g/24hrs),
measured by urine protein creatinine ratio on a random urine sample)
26. Any malabsorption condition.
27. Left Ventricular Ejection Fraction (LVEF) < 50% or below the LLN for the institution
(whichever is higher).
28. Pleural effusion or ascites that causes respiratory compromise (= NCI-CTCAE version
4.03 grade 2 dyspnea)
NOTE: It is not necessary to demonstrate disease progression or imatinib intolerance to
offer the study entrance.
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