E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Colorectal Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the colon or rectum |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To evaluate and compare the efficacy and safety of regorafenib versus placebo in subjects with colorectal cancer (CRC) after curative resection of liver metastasis and completion of all planned chemotherapy.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Eligible subjects must:
1. Be male or female, and ≥ 18 years of age
2. Have a diagnosis of Stage IV CRC with metastases to the liver only and have undergone one of the following three treatment regimens:
-A primary CRC lesion(s) in the colon and/or rectum and synchronous liver metastases, which were treated with surgery with curative intent for both primary and metastatic lesions and at least 3 months of neoadjuvant, adjuvant, or perioperative chemotherapy including a fluoropyrimidine and either oxaliplatin or irinotecan. Total chemotherapy administered, including that administered prior to and after liver resection, should not exceed 6 months.
-A primary CRC lesion(s) in the colon and/or rectum, treated with surgery and at least 3 months of adjuvant chemotherapy with a) a fluoropyrimidine or b) a fluoropyrimidine and oxaliplatin or c) a fluoropyrimidine and irinotecan and > 6 months after completing treatment for primary CRC, developed liver metastases, which were treated with surgery with curative intent and a second course of chemotherapy lasting at least 3 months, including a fluoropyrimidine and either oxaliplatin or irinotecan. The second round of chemotherapy administered for the treatment of liver metastases should not exceed 6 months.
-A primary CRC lesion(s) in the colon and/or rectum, treated with surgery and at least 3 months of chemotherapy, including a) a fluoropyrimidine, b) fluoropyrimidine and oxaliplatin, or c) fluoropyrimidine and irinotecan, and developed liver metastases ≤6 months after completing treatment for primary CRC which were treated with surgery with curative intent. In this case, a second course of chemotherapy is not permitted unless initial adjuvant therapy consisted of fluoropyrimidine monotherapy. Subjects who received fluoropyrimidine alone must have received a second course of chemotherapy with fluoropyrimidine and either oxaliplatin and irinotecan. This second course of chemotherapy may be neoadjuvant, adjuvant, or perioperative. Radiofrequency ablation and chemoembolization are not permitted. Subjects undergoing a planned 2-stage resection of liver metastases may be enrolled into the study.
3. Have tumor tissue (of primary tumor and liver metastases or at least one of the two) available for biomarker analysis (to be collected as soon as possible before or after randomization).
4. Prior to randomization, have histological confirmation that all CRC lesions were adenocarcinoma. Subjects with CRC lesions of other histologic types, including mixed type with predominant adenocarcinoma, will not be eligible to be randomized to study treatment.
5. Prior to randomization, have pathology-proven complete removal of all primary and liver metastatic CRC lesions. Subjects with positive margins will not be eligible for the study.
6. Have had a computed tomography (CT) or magnetic resonance imaging (MRI) scan (chest, abdomen, pelvis and other suspected sites as applicable) to determine eligibility for randomization within 4 weeks prior to randomization (hereafter referred to as the “eligibility scan”)
7. Have absence of disease on the eligibility scan (CT/MRI) by investigator assessment and confirmed by central radiology review
8. Have an Eastern Cooperative Oncology Group performance status of 0 or 1 within 14 days prior to the initiation of study treatment
9. Have adequate bone marrow function, liver function, and renal function, as measured by laboratory assessments conducted within 7 days prior to the initiation of study treatment.
10. Understand, be willing to give consent, and sign the written informed consent form (ICF) prior to undergoing any study-specific procedure.
11. Be willing to give consent and sign the ICF for tumor tissue collection (primary tumor and liver metastases).
12. Be willing to give consent and sign the ICF for the genetic testing unless precluded by local guidelines (eg, Independent Ethics Committee [IEC]/Institutional Review Board [IRB] or Regulatory Authority)
13. If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment.
14. If female and of childbearing potential, or if male, agree to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 8 weeks after the last dose of study drug. |
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E.4 | Principal exclusion criteria |
1. Are taking strong 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).
2. Have used biologic response modifiers, such as granulocyte-colony stimulating factor, within 3 weeks of study entry
3. Have had prior treatment with regorafenib or any other VEGFR-targeting kinase inhibitor.
4. Have had anti-cancer treatment following liver resection that exceeded a duration of 6 months.
5. Have been treated with biologics (eg, antibodies targeting VEGFR or EFGR) after liver resection unless the administration of the biologic started prior to liver resection and continued after liver resection only to complete a pre-specified number of cycles.
6. Completed their last dose of chemotherapy or had their last cancer surgery more than 8 weeks, whichever came later, prior to randomisation.
7. Have extra-hepatic metastatic disease. Suspicious lesions should be rigorously evaluated with other imaging techniques and/or biopsy to exclude extra-hepatic metastatic disease.
8. Have been previously assigned to treatment during this study (subjects permanently withdrawn from study treatment will not be allowed to re-enter the study).
9. Have had prior or concurrent cancer distinct in primary site or histology from CRC within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, nonmelanoma skin cancer, or superficial bladder tumors classified as noninvasive tumor (Ta), carcinoma in situ (Tis), or tumor invades lamina propria (T1).
10. Have had systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and/or hormonal therapy within 4 weeks prior to initiation of study treatment.
11. Have unresolved toxicity higher than National Cancer Institute-Common Terminology for Adverse Events version 4.0 (NCI-CTCAE v 4.0) Grade 1 attributed to any prior therapy/procedure, excluding alopecia and/or oxaliplatin-induced neurotoxicity ≤ Grade 2 and hemoglobin ≥ 9 g/dL as per inclusion criteria.
12. Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment.
13. Are pregnant.
14. Are breastfeeding.
15. Are unable to swallow oral tablets (crushing of study treatment tablets is not allowed).
16. Have congestive heart failure classified as New York Heart Association Class 2 or higher.
17. Have had unstable angina (angina symptoms at rest) or new-onset angina ≤ 3 months prior to screening.
18. Have had a myocardial infarction < 6 months prior to initiation of study treatment.
19. Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin.
20. Have uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90mm Hg) despite optimal medical management.
21. Have pheochromocytoma.
22. Have had arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 6 months prior to the initiation of study treatment.
23. Have an ongoing infection with severity of Grade 2 or above (NCI-CTCAE v 4.0).
24. Have a known history of human immunodeficiency virus infection.
25. Have either active hepatitis or chronic hepatitis B or C requiring treatment with antiviral therapy.
26. Have a seizure disorder requiring medication.
27. Have a history of organ allograft.
28. Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity.
29. Have had a hemorrhage or a bleeding event ≥ Grade 3 (NCI-CTCAE v 4.0) within 4 weeks prior to the initiation of study treatment.
30. Have a nonhealing wound, ulcer, or bone fracture.
31. Have renal failure requiring hemodialysis or peritoneal dialysis.
32. Have dehydration ≥ Grade 1 (NCI-CTCAE v 4.0).
33. Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained.
34. Have persistent proteinuria > 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (≥ Grade 3, NCI-CTCAE v 4.0).
35. Have any other serious or unstable illness, or medical, psychological, or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures or may interfere with the subject’s participation in the study or evaluation of the study results.
36. Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
37. Have any malabsorption condition.
38. Have a close affiliation with the investigational site (eg, be a close relative of the investigator) or be a dependent person (eg, be an employee or student working at the investigational site). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease-free survival (DFS)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint, disease-free survival (DFS) as assessed by the investigator, will be measured by CT/MRI scans obtained at screening and every 3 months during the first 3 years of the study, then 6-monthly for a further year, then yearly until disease recurrence. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All subjects will be followed until death (unless consent for Overall Survival follow-up is withdrawn). |
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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 | Yes |
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 | 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 | 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 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
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 |
Belgium |
Brazil |
Canada |
China |
France |
Germany |
Israel |
Italy |
Japan |
Portugal |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |