Colorectal Cancer Treated With Adjuvant Regorafenib Versus Placebo After Curative Treatment of Liver Metastases in a Randomized, Double-blind, Placebo-Controlled Phase-III STudy

NCT ID: NCT01939223

Last Updated: 2017-10-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-02
• Study Completion Date: 2016-08-29

Brief Summary

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.

Conditions

Colorectal Neoplasms

Keywords

Stage IV colorectal cancer / Liver Metastasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Regorafenib

4 regorafenib tablets taken orally in the morning daily, followed by a low fat meal for 3 weeks on off treatment followed by 1 week off without treatment,Treatment 21 days.

Group Type: EXPERIMENTAL

Regorafenib (Stivarga, BAY73-4506)

Intervention Type: DRUG

Four tablets of 40mg taken orally daily in the morning, dose of 160 mg for 21 days of treatment followed by 7 days without treatment

Placebo

4 placebo tablets taken orally in the morning daily,followed by a low fat meal for 3 weeks on off treatment followed by 1 week off without treatment,Treatment 21 days.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Four tablets taken in the morning orally daily for 21 days of treatment followed by 7 days without treatment

Interventions

Regorafenib (Stivarga, BAY73-4506)

Four tablets of 40mg taken orally daily in the morning, dose of 160 mg for 21 days of treatment followed by 7 days without treatment

Intervention Type: DRUG

Placebo

Four tablets taken in the morning orally daily for 21 days of treatment followed by 7 days without treatment

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Have a history of a primary adenocarcinoma of the colon and / or rectum
• Have a history of Stage IV Colorectal Cancer (CRC) with metastases to the liver only
• Have received at least 3 months ,of neoadjuvant, adjuvant, or perioperative chemotherapy, including a fluoropyrimidine and either oxaliplatin or irinotecan or both for subjects with initial Stage IV CRC which were treated with surgery with curative intent for both primary and metastatic lesions. The total chemotherapy administered, including that administered prior to and after liver resection, should not exceed 9 months. OR Have received surgery with curative intent for primary CRC and at least 3 months ,of neoadjuvant, adjuvant, or perioperative chemotherapy for the primary tumor, including a fluoropyrimidine or a fluoropyrimidine and either oxaliplatin or irinotecan or both

• For subjects with liver metastases developing > 6 months after completing treatment for primary CRC and having undergone surgery with curative intent for liver metastases, a second course of chemotherapy lasting at least 3 months needs to be administered, including a fluoropyrimidine and either oxaliplatin or irinotecan or both. The second course of chemotherapy should not exceed 9 months.
• For subjects who developed liver metastases >/=6 months after completing treatment for primary CRC and having undergone surgery with curative intent for liver metastases, 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 or irinotecan or both, which should not exceed 9 months.For subjects with initial Stage I or II disease, no chemotherapy is required for a primary CRC lesion treated with surgery with curative intent. These subjects must receive chemotherapy for the treatment of liver metastases (which were also treated with surgery with curative intent), which must last at least 3 months, including a fluoropyrimidine and either oxaliplatin or irinotecan or both. The total course of chemotherapy should not exceed 9 months.
• Prior to randomization, have histological confirmation that CRC lesions were adenocarcinoma (subtypes of adenocarcinoma, e.g. mucinous adenocarcinoma are allowed). Subjects with CRC lesions of other histological types, including mixed type with predominant adenocarcinoma, will not be eligible to be randomized to study treatment.
• Have pathology-proven complete removal of all primary and liver metastatic CRC lesions. Subjects with positive margins will not be eligible for the study.
• Have adequate bone marrow function, liver function, and renal function, as measured by the following laboratory assessments conducted within 7 days prior to the initiation of study treatment:

• Total bilirubin </=1.5 times the upper limit of normal (ULN)
• Alanine aminotransferase and aspartate aminotransferase </= 3 times the ULN
• Lipase</=1.5 times the ULN
• Serum creatinine</=1.5 times the ULN
• Carcinoembryonic antigen (CEA)</=3 times the ULN
• Glomerular filtration rate>/=30 mL/min/1.73 m2 according to the Modified Diet in Renal Disease abbreviated formula
• International normalized ratio of prothrombin time and activated partial thromboplastic time </=1.5 times the ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate if no underlying abnormality in coagulation parameters exists per medical history.
• Platelet count >/=100,000 /mm3, hemoglobin >/=9 g/dL, absolute neutrophil count >/= 1500/mm3 without transfusions or granulocyte colony stimulating factor and other hematopoietic growth factors
• Alkaline phosphatase ≤ 2.5 times the ULN
• Have had a CT or 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")
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior to the initiation of study treatment
• If female and of childbearing potential, or if male, agree to use adequate contraception (e.g., 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.

Exclusion Criteria

• Are taking 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).
• Have used biologic response modifiers, such as granulocyte-colony stimulating factor, within 3 weeks prior to signing the ICF.
• Have had prior treatment with regorafenib or any other (vascular endothelial growth factor receptor) VEGFR-targeting kinase inhibitor.
• Have had anti-cancer treatment following liver resection that exceeded a duration of 6 months.
• Have been treated with biologics (eg, antibodies targeting VEGFR or EGFR) 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.
• Completed their last dose of chemotherapy or had their last cancer surgery more than 10 weeks, whichever came later, prior to randomization.
• Have extra-hepatic metastatic disease. Suspicious lesions should be rigorously evaluated with other imaging techniques and/or biopsy to exclude extra-hepatic metastatic disease prior to submitting for central radiology review.
• 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.
• Are pregnant and or breast feeding.
• 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, Stage 0 intramucosal gastric cancer after endoscopic complete removal, or superficial bladder tumors classified as noninvasive tumor (Ta), carcinoma in situ (Tis), or tumor invades lamina propria (T1).
• Have congestive heart failure classified as New York Heart Association Class 2 or higher.Have had unstable angina (angina symptoms at rest) or new-onset angina ≤ 3 months prior to screening. Have had a myocardial infarction < 6 months prior to initiation of study treatment.
• Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin.
• Have uncontrolled hypertension (systolic blood pressure [SBP] greater than140 mmHg or diastolic blood pressure [DBP] greater than 90 mmHg) despite optimal medical management.
• Have pheochromocytoma.
• 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.
• Have a known history of human immunodeficiency virus infection.
• Have either active or chronic hepatitis B or C requiring treatment with antiviral therapy.
• Have a seizure disorder requiring medication.
• Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity.
• 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.
• Have any other serious or unstable illness, or medical, social, or psychological 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

Laguna Hills, California, United States

Los Angeles, California, United States

Los Angeles, California, United States

Los Angeles, California, United States

New Haven, Connecticut, United States

New Orleans, Louisiana, United States

Baltimore, Maryland, United States

Detroit, Michigan, United States

Rochester, Minnesota, United States

Omaha, Nebraska, United States

New Brunswick, New Jersey, United States

Buffalo, New York, United States

New York, New York, United States

Syracuse, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Philadelphia, Pennsylvania, United States

Chattanooga, Tennessee, United States

Germantown, Tennessee, United States

Dallas, Texas, United States

Richmond, Virginia, United States

Kirkland, Washington, United States

Seattle, Washington, United States

Seattle, Washington, United States

Liverpool, New South Wales, Australia

East Melbourne, Victoria, Australia

Bentleigh East, , Australia

Malvern, , Australia

Edegem, , Belgium

Leuven, , Belgium

Liège, , Belgium

Belo Horizonte, Minas Gerais, Brazil

Porto Alegre, Rio Grande do Sul, Brazil

São José do Rio Preto, São Paulo, Brazil

São Paulo, São Paulo, Brazil

Edmonton, Alberta, Canada

Toronto, Ontario, Canada

Sherbrooke, Quebec, Canada

Montreal, , Canada

Fujian Medical University Union Hospital

Fuzhou, Fujian, China

Guangzhou, Guangdong, China

Guangzhou, Guangdong, China

Harbin, Heilongjiang, China

Wuhan, Hubei, China

Changsha, Hunan, China

Xi'an, Shaanxi, China

Xi'an, Shaanxi, China

Kunming, Yunnan, China

Hangzhou, Zhejiang, China

Hangzhou, Zhejiang, China

Beijing, , China

Beijing, , China

Beijing, , China

Beijing, , China

Shanghai, , China

Shanghai, , China

Shanghai, , China

Bordeaux, , France

Brest, , France

Clermont-Ferrand, , France

Lyon, , France

Marseille, , France

Paris, , France

Poitiers, , France

Tours, , France

Villejuif, , France

München, Bavaria, Germany

Frankfurt am Main, Hesse, Germany

Oldenburg, Lower Saxony, Germany

Mainz, Rhineland-Palatinate, Germany

Berlin, , Germany

Haifa, , Israel

Ramat Gan, , Israel

Tel Aviv, , Israel

Foggia, Apulia, Italy

Napoli, Campania, Italy

Reggio Emilia, Emilia-Romagna, Italy

Udine, Friuli Venezia Giulia, Italy

Rome, Lazio, Italy

Brescia, Lombardy, Italy

Milan, Lombardy, Italy

Milan, Lombardy, Italy

Milan, Lombardy, Italy

Florence, Tuscany, Italy

Pisa, Tuscany, Italy

Kashiwa, Chiba, Japan

Sapporo, Hokkaido, Japan

Sapporo, Hokkaido, Japan

Sapporo, Hokkaido, Japan

Akashi, Hyōgo, Japan

Amagasaki, Hyōgo, Japan

Kobe, Hyōgo, Japan

Kasama, Ibaraki, Japan

Yokohama, Kanagawa, Japan

Suita, Osaka, Japan

Takatsuki, Osaka, Japan

Sunto, Shizuoka, Japan

Shimotsuke, Tochigi, Japan

Koto-ku, Tokyo, Japan

Minato-ku, Tokyo, Japan

Mitaka, Tokyo, Japan

Shinagawa, Tokyo, Japan

Shinjuku-ku, Tokyo, Japan

Fukuoka, , Japan

Fukuoka, , Japan

Fukuoka, , Japan

Almada, , Portugal

Porto, , Portugal

Santa Maria da Feira, , Portugal

Alicante, , Spain

Badajoz, , Spain

Barcelona, , Spain

Córdoba, , Spain

Madrid, , Spain

Madrid, , Spain

Madrid, , Spain

Valencia, , Spain

Valencia, , Spain

Royal Marsden NHS Trust (Surrey)

Sutton, Surrey, United Kingdom

Bristol, , United Kingdom

London, , United Kingdom

London, , United Kingdom

Countries

United States; Australia; Belgium; Brazil; Canada; China; France; Germany; Israel; Italy; Japan; Portugal; Spain; United Kingdom

Other Identifiers

2012-004369-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

15983

Identifier Type: -

Identifier Source: org_study_id