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

NCT01939223 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: 159832012-004369-42
• Study Type: interventional
• Target: 25
• Locations: 14 countries
• Sites: 121

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

Outcome Measures

Primary Outcomes (1)

• Disease Free Survival (DFS) as Assessed by the Investigator

  Disease free survival was evaluated by CT / MRI scans as assessed by the investigator, which was defined as the time (in days) from date of randomization to date of first observed radiographic disease recurrence (RECIST 1.1 criteria for measurable and non-measurable disease) or death due to any cause, if death occurred before disease recurrence was documented. For subjects without documented disease recurrence or death at the time of analysis, the DFS time was censored at the date of the last evaluable CT / MRI scan.

  From date of randomization to date of first observed radiographic disease recurrence (RECIST 1.1 criteria for measurable and non-measurable disease) or death due to any cause, if death occurred before disease recurrence was documented.

Secondary Outcomes (1)

• Overall Survival (OS)

  Subjects who experienced disease recurrence (either during treatment or during Active Follow-up), or otherwise withdrew from the study for any reason other than death, were followed for overall survival unless consent was withdrawn.

Study Arms (2)

Regorafenib

EXPERIMENTAL

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.

Drug: Regorafenib (Stivarga, BAY73-4506)

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Regorafenib (Stivarga, BAY73-4506) 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

Regorafenib

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Bayer: lead

Study Sites (121)

Unknown Facility

Laguna Hills, California, 92653, United States

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Los Angeles, California, 90033, United States

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Los Angeles, California, 90089, United States

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Los Angeles, California, 90095, United States

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New Haven, Connecticut, 06520-8064, United States

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New Orleans, Louisiana, 70121, United States

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Baltimore, Maryland, 21201-1595, United States

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Detroit, Michigan, 48202, United States

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Rochester, Minnesota, 55905, United States

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Omaha, Nebraska, 68106, United States

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New Brunswick, New Jersey, 08903-2681, United States

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Buffalo, New York, 14263-0001, United States

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New York, New York, 10021, United States

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Syracuse, New York, 13210, United States

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Duke University Medical Center

Durham, North Carolina, 27710, United States

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Philadelphia, Pennsylvania, 19104, United States

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Chattanooga, Tennessee, 37421, United States

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Germantown, Tennessee, 38138, United States

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Dallas, Texas, 75390, United States

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Richmond, Virginia, 23298-0037, United States

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Kirkland, Washington, 98034, United States

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Seattle, Washington, 98101, United States

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Seattle, Washington, 98109, United States

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Liverpool, New South Wales, 2170, Australia

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East Melbourne, Victoria, 3002, Australia

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Bentleigh East, 3165, Australia

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Malvern, 3144, Australia

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Edegem, 2650, Belgium

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Leuven, 3000, Belgium

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Liège, 4000, Belgium

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Belo Horizonte, Minas Gerais, 30110-090, Brazil

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Porto Alegre, Rio Grande do Sul, Brazil

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São José do Rio Preto, São Paulo, Brazil

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São Paulo, São Paulo, 01246-000, Brazil

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Edmonton, Alberta, T6G 1Z2, Canada

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Toronto, Ontario, M5G 1X8, Canada

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Sherbrooke, Quebec, J1H 5N4, Canada

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Montreal, H2W 1S6, Canada

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Fujian Medical University Union Hospital

Fuzhou, Fujian, 350001, China

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Guangzhou, Guangdong, 510060, China

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Guangzhou, Guangdong, 510655, China

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Harbin, Heilongjiang, China

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Wuhan, Hubei, 430033, China

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Changsha, Hunan, 410008, China

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Xi'an, Shaanxi, 710032, China

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Xi'an, Shaanxi, 710038, China

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Kunming, Yunnan, 650118, China

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Hangzhou, Zhejiang, 310009, China

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Hangzhou, Zhejiang, 310016, China

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Beijing, 100021, China

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Beijing, 100071, China

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Beijing, 100142, China

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Beijing, 100730, China

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Shanghai, 200030, China

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Shanghai, 200032, China

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Shanghai, 200127, China

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Bordeaux, 33076, France

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Brest, 29285, France

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Clermont-Ferrand, 63000, France

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Lyon, 69373, France

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Marseille, 13385, France

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Paris, 75651, France

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Poitiers, 86021, France

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Tours, 37044, France

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Villejuif, 94800, France

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München, Bavaria, 81377, Germany

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Frankfurt am Main, Hesse, 60590, Germany

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Oldenburg, Lower Saxony, 26133, Germany

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Mainz, Rhineland-Palatinate, 55131, Germany

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Berlin, 12200, Germany

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Haifa, 3109601, Israel

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Ramat Gan, 52482, Israel

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Tel Aviv, 64239, Israel

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Foggia, Apulia, 71013, Italy

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Napoli, Campania, 80131, Italy

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Reggio Emilia, Emilia-Romagna, 42123, Italy

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Udine, Friuli Venezia Giulia, 33100, Italy

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Rome, Lazio, 00189, Italy

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Brescia, Lombardy, 25124, Italy

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Milan, Lombardy, 20089, Italy

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Milan, Lombardy, 20133, Italy

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Milan, Lombardy, 20141, Italy

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Florence, Tuscany, 50134, Italy

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Pisa, Tuscany, 56126, Italy

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Kashiwa, Chiba, 277-8577, Japan

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Sapporo, Hokkaido, 006-8555, Japan

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Sapporo, Hokkaido, 060-0004, Japan

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Sapporo, Hokkaido, 060-8648, Japan

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Akashi, Hyōgo, 673-8558, Japan

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Amagasaki, Hyōgo, 660-8511, Japan

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Kobe, Hyōgo, 650-0047, Japan

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Kasama, Ibaraki, 309-1793, Japan

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Yokohama, Kanagawa, 241-8515, Japan

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Suita, Osaka, 565-0871, Japan

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Takatsuki, Osaka, 569-8686, Japan

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Sunto, Shizuoka, 411-8777, Japan

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Shimotsuke, Tochigi, 329-0498, Japan

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Koto-ku, Tokyo, 135-8550, Japan

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Minato-ku, Tokyo, 105-8471, Japan

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Mitaka, Tokyo, 181-8611, Japan

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Shinagawa, Tokyo, 142-8666, Japan

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Shinjuku-ku, Tokyo, 160-8582, Japan

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Fukuoka, 810-8563, Japan

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Fukuoka, 811-1395, Japan

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Fukuoka, 812-8582, Japan

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Almada, 2801-951, Portugal

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Porto, 4200-072, Portugal

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Santa Maria da Feira, 4520-531, Portugal

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Alicante, 03010, Spain

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Badajoz, 06080, Spain

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Barcelona, 08036, Spain

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Córdoba, 14004, Spain

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Madrid, 28007, Spain

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Madrid, 28034, Spain

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Madrid, 28040, Spain

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Valencia, 46009, Spain

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Valencia, 46013, Spain

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Royal Marsden NHS Trust (Surrey)

Sutton, Surrey, SM2 5PT, United Kingdom

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Bristol, BS2 8ED, United Kingdom

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London, SW3 6JJ, United Kingdom

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London, WC1E 6BT, United Kingdom

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MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

regorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Limitations and Caveats

This study was prematurely terminated. Analysis was not performed for primary and secondary outcome measures.

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayer.com

+49 30 300139003

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2013
• First Posted: September 11, 2013
• Study Start: December 2, 2013
• Primary Completion: August 29, 2016
• Study Completion: August 29, 2016
• Last Updated: October 20, 2017
• Results First Posted: October 20, 2017

Record last verified: 2017-09

Locations

US (23); BE (3); AU (4); BR (4); IT (11); IL (3); CA (4); JP (21); GB (4); CN (18); FR (9); DE (5); PT (3); ES (9)