E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
non-resectable pretreated colorectal cancer |
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E.1.1.1 | Medical condition in easily understood language |
on-resectable pretreated colorectal cancer |
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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 |
The primary objective is to investigate circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS). |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: Correlation of baseline as well as surveillance ctDNA results and - Objective Disease Control Rate (DCR) according to RECIST 1.1 Criteria - Progression-Free Survival (PFS) - Safety and tolerability
OS, PFS and DCR will be correlated with the baseline immunoscore from real-time tumor-tissue biopsy.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Age ≥ 18 years. • Life expectancy of at least 12 weeks (3 months). • Eastern Cooperative Oncology Group performance status of 0 or 1 (within14 days prior to the initiation of regorafenib) • Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure. • Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements: • Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) • Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) • Lipase ≤ 1.5 times the ULN • Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer and /or have bone metastases). • Serum creatinine ≤ 1.5 x the ULN • International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x ULN. (Subjects who are prophylactically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care. (See Section 3.3) • Platelet count ≥ 100000 /mm3, hemoglobin (Hb) ≥ 9 g/dL, absolute neutrophil count (ANC) ≥ 1500/mm3. Blood transfusion to meet the inclusion criteria will not be allowed. • Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of regorafenib, and a negative result must be documented before start of regorafenib. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test. The definition of adequate contraception will be based on the judgment of the investigator. • Women of childbearing potential and men must agree to use adequate contraception before entering the program until at least 8 weeks after the last regorafenib 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 • Subject must be able to swallow and retain oral medication.
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E.4 | Principal exclusion criteria |
• Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management. • Active or clinically significant cardiac disease including: • Congestive heart failure – New York Heart Association (NYHA) > Class II. • Active coronary artery disease. • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. • Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization. • Evidence or history of bleeding diathesis or coagulopathy. • Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of regorafenib. • Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of informed consent. • Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from colon cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before randomization are allowed. All cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form). • Patients with phaeochromocytoma. • Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy. • Ongoing infection > Grade 2 NCI-CTCAE v4.0. • Symptomatic metastatic brain or meningeal tumors. • Presence of a non-healing wound, non-healing ulcer, or bone fracture. • Major surgical procedure or significant traumatic injury within 28 days before start of regorafenib • Renal failure requiring hemo-or peritoneal dialysis. • Dehydration Grade >1 NCI-CTCAE v4.0. • Patients with seizure disorder requiring medication. • Persistent proteinuria > Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample). • Interstitial lung disease with ongoing signs and symptoms at the time of informed consent. • Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 4.0 Grade 2 dyspnea). • History of organ allograft (including corneal transplant). • Known or suspected allergy or hypersensitivity to any of regorafenib, regorafenib classes, or excipients of the formulations given during the course of this trial. • Any malabsorption condition. • Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results. • Subjects taking strong cytochrome P (CYP) 3A4 inhibitors (eg, clarithromycin,indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort). • Women who are pregnant or breast-feeding. • Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial participation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 36 months from the start of study. |
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E.5.2 | Secondary end point(s) |
Correlation of baseline as well as surveillance ctDNA results and - Objective Disease Control Rate (DCR) according to RECIST 1.1 Criteria - Progression-Free Survival (PFS) - Safety and tolerability |
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Translational Pilot Study |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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Last visit of last active patient |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |