E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The present proposal is aimed to evaluate the efficacy and safety of regorafenib as maintenance therapy in increasing the efficacy of the best available therapy for first line treatment fluoropirimidine based chemotherapy , any variant, in combination with either cetuximab or panitumumab) of RAS wild type metastatic colorectal cancer patients. |
Ziel der vorliegenden Studie ist die Evaluierung der Wirksamkeit und Sicherheit von Regorafenib als Erhaltungstherapie zur Erhöhung der Wirksamkeit der besten verfügbaren Therapie zur Erstbehandlung (Fluoropirimidine basierte Chemotherapie in jeder Variante, in Kombination mit entweder Cetuximab oder Panitumumab) für Patienten mit metastasiertem Kolorektalkarzinom des Typs RASwild. |
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E.1.1.1 | Medical condition in easily understood language |
Regorafenib as maintenance therapy of RAS wild type metastatic
colorectal cancer patients. |
Regorafenib als Erhaltungstherapie für Patienten mit metastasiertem RAS Wildtyp Kolorektalkarzinom. |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
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 objective of this study is to evaluate efficacy and safety of regorafenib in the maintenance of the response in patients with metastatic colorectal (CRC) RAS wild type after first line therapy
(fluoropirimidine-based plus anti-EGFR Abs). The primary efficacy endpoint of this study is Progression Free Survival (PFS) defined as the time(days) from randomization for maintenance therapy with study drug to PD or death whichever comes first. |
Ziel dieser Studie ist die Evaluierung der Wirksamkeit und Sicherheit von Regorafenib als Erhaltungstherapie zur Erhöhung der Wirksamkeit der besten verfügbaren Therapie zur Erstbehandlung (Fluoropirimidine basierte Chemotherapieplus EGFR Abs) für Patienten mit metastasiertem Kolorektalkarzinom des Typs RASwild. Der primäre Endpunkt ist das Progression Free Survival (PFS) definiert als die Zeitspanne (Anzahl der Tage) vom Zeitpunkt der Randomierierung bis zur Progression der Krankheit oder bis zum Tod, je nachdem welches Ereignis zuerst eintritt. |
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E.2.2 | Secondary objectives of the trial |
- Overall survival (OS)
- Safety Profile
- Biomarker correlative studies |
- Überleben
- Verträglichkeit / Nebenwirkungsprofil
- Biomarker-Korrelationsstudien |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Signed informed consent obtained before any study specific procedures. Patients must be able to understand and willing to sign a written informed consent.
•Male or female patients > 18 years
•Histological or cytological documentation of adenocarcinoma of the colon or rectum
•Genetic diagnosis of RAS(hot spot mutations KRAS codon 2-3-4 and NRAS at least codon 2-3) wild type tumor .
•Previous standard first line treatment defined as fluoropirimidine based chemotherapy (any variant) in combination with either cetuximab or panitumumab for a minimum of 4 months and a maximum of 8 months.
•Patients that have achieved either partial response (PR) , complete response (CR) or stable disease (SD) at the completion of the first line treatment after a minimum of 4 months (8 cycles) and a maximum of 8 months (16 cycles) .
•Patients with PR/SD must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST criteria, version 1.1).
•Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.
•Life expectancy of at least 6months.
•Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
o Total bilirubin < 1.5 x the upper limit of normal (ULN).
o Alanine transaminase (ALT) and aspartate aminotransferase (AST) <3 x ULN (<5 x ULN for patients with liver involvement of their cancer).
o Serum creatinine< 1.5 x the ULN.
o Estimated creatinine clearance (CLcr) ≥ 30 mL/min as calculated using the Cockcroft-Gault equation.
o INR/PTT < 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g. heparin, will be allowed to participate provided 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.
o Platelet count ¬> 100000 /mm3, Hemoglobin (Hb) > 9 g/dl, Absolute neutrophil count (ANC) > 1500/mm3
o Alkaline phosphatase limit < 2.5 x ULN (<5 x ULN for patients with liver involvement of their cancer)
o Lipase < 1.5 x ULN
•Women of childbearing potential and men must agree to use adequate contraception before entering the program until at least 8 weeks after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.
•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.
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E.4 | Principal exclusion criteria |
•Prior treatment with regorafenib.
•Interruption of the first line treatment for progressive disease or in which progressive disease was diagnosed prior to entry into this study.
•Assumption of strong cytochrome P (CYP) CYP3A4 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) (see Section 13.1)
•Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer 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), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
•Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
•Congestive heart failure > 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 medication.
•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).
•Patients with phaeochromocytoma.
•Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication.
•Ongoing infection > grade 2 NCI-CTC version 3.0.
•Known history of human immunodeficiency virus (HIV) infection.
•Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiretroviral therapy.
•Patients with seizure disorder requiring medication.
•Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)
•History of organ allograft
•Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks of start of study medication.
•Non-healing wound, ulcer, or bone fracture.
•Renal failure requiring hemo-or peritoneal dialysis.
•Dehydration NCI-CTC version 3.0 grade > 1.
•Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
•Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
•Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
•Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
•Patients unable to swallow oral medications
•Persistent proteinuria of CTC Grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).
•Any malabsorption condition
•Unresolved toxicity higher than NCI-CTCAE (version 3.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia,oxaliplatin induced neurotoxicity and anti-EGFR Ab induced skin toxicity ≤ Grade 1
•Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free Survival (PFS) |
Progressionsfreies Überleben |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Overall Survival
Safety
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Überleben
Verträglichkeit |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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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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 |