This clinical study evaluates and compares the efficacy and safety of Regorafenib versus placebo in patients with colorectal cancer after curative resection of liver metastasis and completion of all planned chemotherapy.
- Conditions
- Metastatic Colorectal CancerMedDRA version: 14.1Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2012-004369-42-FR
- Lead Sponsor
- Bayer HealthCare AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 750
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 conduct
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 hepatiti
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: 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.<br>;Secondary Objective: Not Applicable;Primary end point(s): Disease-free survival (DFS) <br>;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.
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Overall survival;Timepoint(s) of evaluation of this end point: All subjects will be followed until death (unless consent for Overall Survival follow-up is withdrawn).