E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic and /or unresectable gastrointestinal tumors (GIST) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051066 |
E.1.2 | Term | Gastrointestinal stromal tumour |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062427 |
E.1.2 | Term | Gastrointestinal stromal tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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). |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 </= 1.5 x the upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL).
-Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 3.0 x ULN (</= 5 x ULN for subjects with liver involvement of their GIST).
-Lipase </= 1.5 x the ULN
-Serum creatinine </= 1.5 x the ULN.
-Glomerular filtration rate (GFR) >/= 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) </= 1.5 x ULN.
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 standard of care.
-Platelet count >/= 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 </= 2.5 x ULN (</= 5 x ULN for subjects whose cancer involves their liver).
8.Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure-related toxicity (except alopecia and anemia).
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E.4 | Principal 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 NCI-CTCAE version 4.0 grade >/= 1.
23.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.
24.Known hypersensitivity to the study drug, study drug class, or excipients in the formulation.
25.Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study.
26.Interstitial lung disease with ongoing signs and symptoms at the time of screening.
27.Subjects unable to swallow oral medications.
28.Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).
29.Any malabsorption condition.
30.Close affiliation with the investigational site, eg, a close relative of the investigator or dependent person (eg, employee of or student at the investigational site who would have access to study records and eCRF data).
31.Unresolved toxicity higher than NCI-CTCAE version 4.0 grade 1 (excluding alopecia and anemia) attributed to any prior therapy/procedure.
32.Concomitant participation in another clinical study.
33.Left ventricular ejection fraction (LEVF) < 50% or below the LLN for the institution (whichever is higher).
34.Pleural effusion or ascites that causes respiratory compromise (>/= CTC Grade 2 dyspnea
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis will be performed when approximately 144 PFS events are observed. |
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E.5.2 | 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. |
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E.5.2.1 | 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%. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
Austria |
Belgium |
Canada |
China |
Finland |
France |
Germany |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Poland |
Singapore |
Spain |
United Kingdom |
United States |
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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
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For each participating European Union (EU) country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last subject for all centers in the respective country has occurred.
As the primary endpoint of this study is event-based, the end of the study as a whole will only be reached when this endpoint has been achieved in subjects in all participating centers (EU and non-EU).
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |