Clinical trial NCT02664077: A Study Evaluating Regorafenib Following Completion of Standard Chemotherapy for Patients With Colon Cancer
Official title: A Phase III Randomized Placebo-Controlled Study Evaluating Regorafenib Following Completion of Standard Chemotherapy for Patients With Stage III Colon Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Stage III (IIIB or IIIC) Colon Cancer
Keywords: NSABP
Colon cancer
Regorafenib
Stage III
Adjuvant therapy
Lead sponsor: NSABP Foundation Inc
Sponsor class: NETWORK
Collaborators: name: Bayer
First posted: 2016-01-26
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a randomized, double-blind, post-chemotherapy, adjuvant phase III clinical trial. The primary aim of this study is to determine the value of regorafenib in improving disease-free survival (DFS). Patients with Stage III (IIIB or IIIC) colon cancer as defined by the 7th Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual are randomized 1:1 to placebo or the experimental agent regorafenib following completion of at least four months of standard adjuvant therapy (e.g., 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) , capecitabine, oxaliplatin (CapeOx), and other).

Detailed description: The primary aim of this study is to determine the value of regorafenib in improving DFS. The secondary aims are to evaluate the dose tolerance and long term toxicity of two years of regorafenib following standard adjuvant therapy, and to evaluate the effect of the use of regorafenib in overall survival (OS).

Eligible patients in this double-blind study will be randomized to take either regorafenib 120 mg or placebo orally, once daily for 21 consecutive days of a 28 day cycle for 26 cycles (2 years).

Accrual for this study will be approximately 1118 randomized patients. These 1118 patients will provide approximately 313 DFS events at the time of primary analysis. An initial futility analysis will be performed when 312 patients have been on study at least 3 months. The decision to continue the trial will be determined by success of both early stopping endpoints defined as follows:

* The toxicity profile of regorafenib compared to placebo is acceptable.
* The regorafenib regimen is tolerable for prolonged administration.

An estimated compliance rate of 60% at 6 months for regorafenib will be required for continuation of the study.

If toxicity is acceptable and compliance with regorafenib is at least 60% nominally, then accrual will continue.

The second futility analysis will be conducted when approximately 67 DFS events are observed. Trial conduct and accrual will continue unless the primary endpoint (DFS) trends too far in the opposite direction (hazard ratio greater than or equal to 1.1).

Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

NSABP C-13 will include a Behavioral and Health Outcomes correlative science component. A C-13 Quality of Life (QOL) questionnaire will be administered at baseline (after consent and prior to randomization) and at 3 months, 6 months, 12 months, 18 months, 24 months, and 30 months.

Submission of blood samples for C-13 correlative science studies will be a study requirement for all patients. Submissions will also include archived primary tumor tissue from the resected colon primary. Blood samples for pharmacokinetics (PK) will be collected on Day 15 of Cycle 1 and Day 15 of Cycle 2, with additional blood samples for biomarkers collected at various time points for future analysis.

Eligibility criteria: Inclusion Criteria:

* The Eastern Cooperative Oncology Group (ECOG) performance status must be 0-1
* There must be histologic confirmation of high risk, adenocarcinoma of the colon defined as AJCC 7th Edition Stage IIIB or IIIC.
* The patient must have had an en bloc complete gross resection of tumor (curative resection) by open laparotomy or laparoscopically-assisted colectomy. The distal extent of the tumor must have been greater than or equal to 12 cm from the anal verge. (Patients who have had a two-stage surgical procedure to first provide a decompression colostomy and then in a later procedure to have a surgical resection are eligible.)
* Imaging (positron emission tomography/computed tomography (PET/CT) scan, CT scan, or magnetic resonance imaging (MRI)) of chest, abdomen, and pelvis must be performed within 90 days prior to randomization and must demonstrate no evidence of metastatic disease. If findings noted in imaging study reports are equivocal, the determination of whether or not the findings represent metastatic disease will be at the investigator's discretion.
* The patient must be able to swallow oral medication.
* The patient must have completed at least 4 months of adjuvant chemotherapy (i.e., FOLFOX, CapeOx, or other, such as 5-fluorouracil, leucovorin, oxaliplatin (FLOX), 5-fluorouracil/leucovorin (5FU/LV), capecitabine).
* The interval between completion of standard adjuvant chemotherapy and randomization must be less than or equal to 60 days.
* Blood counts performed within 28 days prior to randomization must meet the following criteria:

  * Absolute neutrophil count (ANC) must be greater than or equal to 1500/mm3;
  * platelet count must be greater than or equal to 100,000/mm3; and
  * hemoglobin must be greater than or equal to 9 g/dL.
* The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to randomization must be met:

  * total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN); and
  * alkaline phosphatase must be less than or equal to 2 x ULN; and
  * Asparate aminotransferase (AST) and alanine aminotransferase (ALT) must be less than or equal to 2 x ULN for the lab. (Note: If AST and/or ALT greater than ULN, serologic testing for Hepatitis B and C must be performed and results must be negative.)
* Lipase performed within 28 days of randomization must be less than or equal to 1.5 x ULN for the lab.
* Serum creatinine performed within 28 days of randomization must be less than or equal to 1.5 x ULN for the lab.
* Urinalysis dipstick for urinary protein performed within 28 days prior to randomization must be 0-1+ protein. If urine dipstick result is greater than or equal to 2+ protein, a 24-hour urine protein must be less than 1.0 g/24 hours.
* Glomerular filtration rate (GFR) must be greater than or equal to 30 mL/min/1.73 m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
* International normalized ratio of prothrombin time must be less than or equal to 1.5 times the ULN. Patients 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.
* Patients (male or female) of reproductive potential must agree to use an effective method of contraception (as discussed with treating physician) from the time consent is signed, during study therapy, and for at least 90 days after the last dose of study therapy.
* Patients with prior malignancies are eligible if they have been disease-free for at least 5 years and are deemed by their physician to be at low risk for recurrence. Patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years of randomization.

Exclusion Criteria:

* Isolated, distant, or non-contiguous intra-abdominal metastases, even if resected.
* Colon cancer other than adenocarcinoma (e.g., sarcoma, lymphoma, carcinoid).
* Prior history of invasive adenocarcinoma of colon or rectum.
* Patients with active autoimmune disease. (Patients with endocrine autoimmune diseases requiring replacement therapy alone are allowed.)
* Gastroduodenal ulcer(s) determined by endoscopy to be active.
* Any malabsorption condition.
* Known history of human immunodeficiency virus (HIV) infection or chronic or active hepatitis B or hepatitis C requiring treatment with antiviral therapy.
* Any concomitant systemic therapy or radiation therapy initiated for this malignancy.
* Active infection, or chronic infection requiring chronic suppressive antibiotics.
* Persistent CTCAE v4.0 greater than or equal to grade 2 diarrhea regardless of etiology.
* Know history of allografts (including corneal transplant).
* Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids), or any other immunosuppressive drugs.
* Any significant bleeding (greater than or equal to grade 3, hemorrhage) that is not related to the primary colon tumor within 6 months before randomization.
* Any of the following cardiac conditions:

  * documented New York Heart Association (NYHA) Class III or IV congestive heart failure;
  * myocardial infarction within 6 months prior to randomization;
  * unstable angina (angina symptoms at rest) within less than or equal to 3 months prior to randomization; and
  * clinically significant symptomatic arrhythmia despite anti-arrhythmic therapy.
* Uncontrolled blood pressure (systolic pressure greater than 150 mmHg or diastolic pressure greater than 90 mmHg on repeated measurements).
* Symptomatic brain or meningeal tumors.
* Patients with seizure disorder requiring medication.
* Presence of non-healing wound, non-healing ulcer, or bone fracture.
* Symptomatic interstitial lung disease or definitive evidence of interstitial lung disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen.
* Arterial or venous thrombotic or embolic events such as cerebral vascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before randomization (except for adequately treated catheter-related venous thrombosis occurring within 6 months before randomization).
* Symptomatic peripheral ischemia.
* Psychiatric or addictive disorders or other conditions or unresolved toxicities of prior therapy greater than grade 2 that, in the opinion of the investigator, would preclude the patient from meeting the study requirements, or interfere with interpretation of study results.
* Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be performed within 14 days prior to randomization according to institutional standards for women of childbearing potential.)
* Major surgery (including ostomy reversal), open biopsy or significant trauma injury, within 28 days prior to randomization.
* Anticipation of need for major surgical procedures during the course of study.
* Known hypersensitivity to study drug, study drug classes or excipients of the formulation.
* Use of any vascular endothelial growth factor (VEGF) targeted therapy or previous use of regorafenib.
* Patients taking strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) who cannot interrupt therapy from the time the C-13 consent is signed through 30 days after the last dose of study therapy.
* Patients taking herbal remedies (e.g., St. John's Wort \[Hypericum perforatum\]) who cannot interrupt therapy from the time the C-13 consent is signed through 30 days after the last dose of study therapy.
* Use of immune modulators and/or any immunosuppressive drugs.
* Use of any investigational agent within 28 days of randomization.
* Patients receiving erythropoiesis-stimulating agents or other hematopoietic growth factors.

Primary outcomes:
measure: Disease-free survival (DFS) - time from randomization until first colon cancer recurrence, second primary colon cancer, or death due to any cause.
timeFrame: Beginning at day 1 of cycle 3 (each cycle = 28 days) and every 6 months until study closure about 10 years
Secondary outcomes:
measure: Overall Survival (OS) - time from randomization until death from any cause.
timeFrame: Day 1 of every cycle of chemotherapy then 30 days post study therapy, then every 6 months (years 3-5) then yearly (years 6 & 7)
measure: Toxicity - frequency and severity of adverse events categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0)
timeFrame: Every study visit through 30 days following study therapy
measure: Compliance - Time to discontinuation of study therapy.
timeFrame: Every study visit through discontinuation of study therapy, assessed for up to 24 months
measure: Correlative Science - Biomarker evaluations
timeFrame: Before randomization, prior to beginning Cycle 6, every 6 months through year 5, and at the end of study therapy (maximum of 2 years).
measure: Correlative Science - Pharmacokinetics - Plasma regorafenib concentrations
timeFrame: Day 15 of Cycle 1 and Cycle 2 of study therapy.
measure: Correlative Science - Pharmacodynamics
timeFrame: Day 15 of Cycle 1 and Cycle 2 of study therapy.
measure: Compare the symptoms experienced by patients receiving regorafenib to patients receiving placebo during treatment as measured by Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
timeFrame: Baseline, 3 months, 6 months, 12 months, 18 months, 24 months and 6 months after discontinuation of protocol therapy
Other outcomes:
Locations:
city: Orange
country: United States
facility: St. Joseph Hospital of Orange
state: California
city: Santa Rosa
country: United States
facility: St. Joseph Heritage Healthcare
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente Medical Center - Vallejo
state: California
city: Denver
country: United States
facility: Colorado Cancer Research Program
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Savannah
country: United States
facility: Memorial Health University Medical Center
state: Georgia
city: Decatur
country: United States
facility: Cancer Care Specialists of Illinois - Decatur Memorial Hospital
state: Illinois
city: Naperville
country: United States
facility: Edward Hospital Cancer Center
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: South Bend
country: United States
facility: Northern Indiana Cancer Research Consortium
state: Indiana
city: Cedar Rapids
country: United States
facility: Oncology Associates at Mercy Medical Center
state: Iowa
city: Davenport
country: United States
facility: Genesis Medical Center - West Campus
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Waterloo
country: United States
facility: Covenant Cancer Treatment Center
state: Iowa
city: Louisville
country: United States
facility: Norton Cancer Institute, Norton Healthcare Pavilion
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: Pittsfield
country: United States
facility: Berkshire Medical Center Cancer and Infusion Center
state: Massachusetts
city: Lansing
country: United States
facility: Breslin Cancer Center
state: Michigan
city: Saint Louis Park
country: United States
facility: Metro Minnesota Community Oncology Research Consortium
state: Minnesota
city: Omaha
country: United States
facility: Missouri Valley Cancer Consortium
state: Nebraska
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation, Inc.
state: Nevada
city: Camden
country: United States
facility: MD Anderson Cancer Center at Cooper
state: New Jersey
city: Long Branch
country: United States
facility: Monmouth Medical Center
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Toms River
country: United States
facility: Community Medical Center
state: New Jersey
city: Cary
country: United States
facility: Waverly Hematology Oncology
state: North Carolina
city: Gastonia
country: United States
facility: CaroMont Regional Medical Center
state: North Carolina
city: Hendersonville
country: United States
facility: Margaret R. Pardee Memorial Hospital
state: North Carolina
city: Pinehurst
country: United States
facility: First Health of the Carolinas Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Columbus
country: United States
facility: James Cancer Hospital and Solove Research Institute at the Ohio State University Comprehensive Cancer Center
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Center
state: Ohio
city: Abington
country: United States
facility: Abington Hospital -Jefferson South
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers
state: Pennsylvania
city: Sayre
country: United States
facility: Guthrie Medical Group, PC
state: Pennsylvania
city: Scranton
country: United States
facility: Scranton Hematology Oncology
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital - McGlinn Cancer Institute
state: Pennsylvania
city: Anderson
country: United States
facility: AnMed Health Cancer Center
state: South Carolina
city: Florence
country: United States
facility: McLeod Cancer Center for Treatment and Research
state: South Carolina
city: Kingsport
country: United States
facility: Wellmont Medical Associates Oncology and Hematology
state: Tennessee
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center
state: Tennessee
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Green Bay
country: United States
facility: Green Bay Oncology, Ltd. - St. Vincent Hospital
state: Wisconsin
Study officials:
affiliation: NSABP Foundation
name: Norman Wolmark, MD
role: PRINCIPAL_INVESTIGATOR
References: