E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic adenocarcinoma of the colon or rectum (metastatic CRC) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
to provide regorafenib to subjects diagnosed with metastatic colorectal cancer who have failed all approved standard therapies
to assess the safety of regorafenib
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E.2.2 | Secondary objectives of the trial |
to assess progression free survival (PFS)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Male or female subjects ³ 18 years of age.
•Life expectancy of at least 3 months
•Histological or cytological documentation of adenocarcinoma of the colon or rectum. All other histological types are excluded.
•Subjects with metastatic colorectal cancer (Stage IV).
•Progression during or within 3 months following the last administration of approved standard therapies which must include fluoropyrimidine, oxaliplatin, irinotecan,bevacizumab and cetuximab/panitumumab (if KRAS WT) (WT: wild type)
•ECOG Performance Status of ≤ 1 (ECOG: Eastern Cooperative Oncology Group)
•Adequate bone marrow, liver and renal function
•Women of childbearing potential and men must agree to use adequate contraception
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E.4 | Principal exclusion criteria |
•Prior treatment with regorafenib.
•Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication treatment
•Pregnant or breast-feeding subjects.
•Congestive heart failure ³ New York Heart Association (NYHA) class 2.
•Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
•Myocardial infarction less than 6 months before start of study drug.
•Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
•Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
•Pleural effusion or ascites that causes respiratory compromise (³ CTCAE Grade 2 dyspnea). (CTCAE: common terminology criteria for adverse events)
•Ongoing infection > Grade 2 CTCAE v. 4.0.
•Known history of human immunodeficiency virus (HIV) infection.
•Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
•Subjects with seizure disorder requiring medication.
•Subjects with evidence or history of any bleeding diathesis, irrespective of severity.
•Any hemorrhage or bleeding event ³ CTCAE Grade 3 within 4 weeks prior to the start of study medication.
•Non-healing wound, ulcer, or bone fracture.
•Renal failure requiring hemo-or peritoneal dialysis.
•Dehydration CTCAE v. 4.0 Grade ³ 1.
•Interstitial lung disease with ongoing signs and symptoms
•Persistent proteinuria of CTCAE Grade 3 (>3.5g/24 hours).
•Any malabsorption condition.
•Unresolved toxicity higher than CTCAE (v. 4.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neurotoxicity £ Grade 2.
•Concomitant participation or participation within the last 30 days in another clinical trial
•Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 4 weeks (or within 6 weeks for mitomycin C) before starting to receive study medication.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be safety
Safety Analysis Set (SAF) : the population for the safety analyses is the SAF. All subjects who received at least one dose of regorafenib belong to the SAF.
•Descriptive summary tables will be presented on all safety parameters.
•Subjects will be monitored for adverse events using the NCI-CTCAE version 4.0. (NCI: National Cancer Institute)
•Treatment emergent adverse events and safety laboratory parameters will be summarized by NCI-CTCAE version 4.0 grade and by MedDRA terminology. A treatment-emergent AE is defined as any event arising or worsening after the start of study drug administration until 30 days after the last study medication.
•AEs that caused subject withdrawal, dose reduction, or interruption will be summarized.
•Patients who die during the study will be summarized and listed.
•Patients with SAEs will be summarized and listed.
•Adverse events leading to discontinuation will be summarized and listed.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Last patient last visist date (no event-driven primary completion date) |
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E.5.2 | Secondary end point(s) |
PFS is the only efficacy variable to be analyzed in this study.
The population for the efficacy analysis is the FAS. All subjects assigned to treatment belong to the FAS.
•The Kaplan-Meier curve for PFS and the
Kaplan-Meier estimate of median time to PFS with its confidence interval (CI)
•PFS proportions at 3, 6, 9, 12, etc months with CIs
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Last patient last visist date ( no event-driven primary completion date) |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 97 |
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 |
Australia |
Austria |
Belgium |
Canada |
Czech Republic |
Finland |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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According to the European Union (EU) Clinical Trial Directive for each participating European Union (EU) country the end of the study will be reached when the last visit of the last subject for all centers in the respective country has occurred.
Primary Completion is the same as LPLV, no early end point |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |