E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Colorectal Carcinoma |
|
E.1.1.1 | Medical condition in easily understood language |
Metastatic Colorectal Carcinoma |
|
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 | LLT |
E.1.2 | Classification code | 10010036 |
E.1.2 | Term | Colorectal carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10061451 |
E.1.2 | Term | Colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 evaluate efficacy and safety of regorafenib in patients with metastatic colorectal cancer (CRC) who have progressed after standard therapies.
The primary efficacy endpoint of this study is Overall survival
|
|
E.2.2 | Secondary objectives of the trial |
The secondary efficacy endpoints of this study are Progression free survival, objective tumor response rate and Disease control rate.
|
|
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 of age.
• Histological or cytological documentation of adenocarcinoma of the colon or rectum.
All other histological types are excluded.
• Patients 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 or panitumumab (if KRAS WT). Patients treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy. Patients who progress more than 6 months after completion of oxaliplatin containing adjuvant treatment must be retreated with oxaliplatin-based therapy to be eligible. Patients who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease will also be allowed into the study. Patients with an unknown KRAS status at screening must have received prior anti-EGFR treatment.
• Metastatic CRC patients must have measurable or non 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 3 months.
• Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months 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.
• 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) ≤ 2.5 x ULN
(≤5 x ULN for patients with liver involvement of their cancer).
o Amylase and lipase ≤ 1.5 x the ULN
o Serum creatinine ≤ 1.5 x the ULN.
o Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the MDRD (Modified diet in renal disease) abbreviated formula
o INR/PTT ≤ 1.5 x ULN (Patients who are being therapeutically anti-coagulated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in this parameter 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.)
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)
|
|
E.4 | Principal exclusion criteria |
• Prior treatment with regorafenib.
• Previous assignment to treatment during this study. Patients permanently withdrawn from study treatment participation will not be allowed to re-enter the study.
• 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)].
• Extended field radiotherapy within 4 weeks or limited field radiotherapy within 2 weeks prior to randomization. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.
• 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 > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
• Patients with phaeochromocytoma.
• Pleural effusion or ascites that causes respiratory compromise (≥ CTC Grade 2 dyspnea).
• 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.
• Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
• Patients with seizure disorder requiring medication.
• Any history of or currently known brain metastases.
• History of organ allograft
• Patients with evidence or history of any bleeding diasthesis, irrespective of severity.
• Any hemorrhage or bleeding event ≥ 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 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
• 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 that would have access to study records and eCRF data)
• Unresolved toxicity higher than NCI-CTCAE (version 3.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity ≤Grade 2
• 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint: Overall survival (OS), improvement from 4.5 to 6 months median OS (33.3% improvement, HR of 0.75) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Will be evaluated when there are 582 events/deaths |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
Progression free survival
Objective tumor response rate
Disease control rate
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Will be evaluated when there are 582 events/deaths |
|
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 | Information not present in EudraCT |
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 |
Belgium |
Canada |
China |
Czech Republic |
France |
Germany |
Hungary |
Israel |
Italy |
Japan |
Netherlands |
Spain |
Switzerland |
Turkey |
United States |
|
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
|
The end of the study will be reached when the last visit of the last patient for all centers in the respective country has occurred. However, 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 patients in all participating centers (EU and non-EU). |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
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 |