Metastatic and /or unresectable gastrointestinal tumors (GIST) MedDRA version: 14.0 Level: PT Classification code 10051066 Term: Gastrointestinal stromal tumour System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 14.0 Level: LLT Classification code 10062427 Term: Gastrointestinal stromal t
Conditions
Sponsors
Bayer HealthCare AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Signed informed consent obtained before any study specific procedures. Subjects must be able to understand and willing to sign a written informed consent. 2.Male or female subjects 18 years of age or older. 3.Subjects with histologically confirmed metastatic and/or unresectable GIST. 4.At least imatinib and sunitinib as prior treatment regimens, with objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib therapy. Additionally, disease progression or intolerance to other systemic therapies, as well as investigational new agents, is allowed, except prior treatment with any other vascular endothelial growth factor receptor (VEGFR) inhibitor. 5.Subjects must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. 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 enrollment. 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 /= 30 ml/min/1.73 m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula. -International normalized ratio and partial thromboplastin time (INR and PTT) /= 100000/mm3, hemoglobin (Hb) >/= 9.0 g/dl, absolute neutrophil count (ANC) >/=1500/mm3. Transfusion of subjects to meet the inclusion criteria will not be allowed. -Alkaline phosphatase limit =65 years) yes F.1.3.1 Number of subjects for this age range 75
Exclusion criteria
Exclusion criteria: 1.Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study. 2.Prior treatment with any vascular endothelial growth factor receptor (VEGFR) inhibitor except sunitinib. 3. Subjects who have received: - any other approved tyrosine kinase inhibitor within 1 week or a minimum of 5 drug half-lives, whichever is longer (i.e. within 7 days for imatinib, or within 10 days for sunitinib). - any other investigational new drugs within 4 weeks or 5 drug half-lives (if drug half-life in subjects is known), whichever is shorter. (as of Amd 1) 4.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]). 5.Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication. 6.Pregnant or breast-feeding subjects. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of study medication and a negative result must be documented before start of study medication. Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) since signing of the informed consent form until at least 3 months after the last study drug administration. The definition of adequate contraception will be based on the judgment of the treating investigator or a designated associate. 7.Congestive heart failure New York Heart Association (NYHA) >/= class 2. 8.Unstable angina (angina symptoms at rest, new-onset angina, ie, within the last 3 months) or myocardial infarction (MI) within the past 6 months before start of study medication. 9.Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted). 10.Uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management). 11.Subjects with pheochromocytoma. 12.Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of study drug. 13.Venous thrombotic events such as deep vein thrombosis within the 3 months before start of study drug 14.Ongoing infection > grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. 15.Known history of human immunodeficiency virus (HIV) infection. 16.Subjects with seizure disorder requiring medication. 17.Symptomatic metastatic brain or meningeal tumors 18.History of organ allograft. 19.Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event >/= NCI-CTCAE version 4.0 grade 3 or higher within 4 weeks prior to the start of study drug. 20.Non-healing wound, ulcer, or bone fracture. 21.Renal failure requiring hemo- or peritoneal dialysis. 22.Dehydration N
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this phase III study in subjects with metastatic and/or unresectable GIST who have progressed after therapy with at least imatinib and sunitinib is to compare the treatment groups in terms of Progression-Free Survival (PFS), per blinded central radiology review, according to modified (as of Amd 1) Response Evaluation Criteria in Solid Tumors RECIST criteria (version 1.1).;Secondary Objective: The secondary objectives are to compare the regorafenib and placebo treatment groups in terms of overall survival (OS), time to progression (TTP), disease control rate (DCR), tumor response rate (RR), duration of response (DOR), and safety of regorafenib.;Primary end point(s): The primary efficacy endpoint is Progression-Free Survival (PFS), per blinded central radiology review; the analysis will be performed when approximately 122 PFS events are observed. Based on the overrecruitment of 29 subjects to 199 total randomized subjects, the target number of PFS events is increased to maintain the grade of maturity of the study. The final analysis will be performed using one-sided alpha of 0.01 when at least 144 PFS events have been observed.;Timepoint(s) of evaluation of this end point: The analysis will be performed when approximately 144 PFS events are observed. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Overall survival will be analyzed with the same log-rank test as PFS. The final analysis of OS will be performed when approximately 136 events have been observed. 136 OS events will provide 80% power to detect a 67% increase when a 1-sided alpha of 0.025 is used. At the time of the PFS analysis an interim analysis of OS will be performed. An O'Brien-Fleming-type alpha spending function approach will be used for determination of significance thresholds so that the overall 1-sided alpha for OS is 0.025 or less.;Timepoint(s) of evaluation of this end point: As 199 subjects were randomized instead of the originally planned 170 subjects, the number of survival events will be increased by the same ratio as the number of PFS events. The final analysis of OS will be performed when approximately 160 events have been observed. As a consequence, the power will be increased from 80% to 86%. | — |
Countries
Austria, Belgium, Canada, China, Finland, France, Germany, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Singapore, Spain, United Kingdom, United States
Contacts
Public ContactCTPTeam/Ref:"EU CTR"/S102-Room 156
Bayer HealthCare AG
Outcome results
None listed