including Dallas, TX, Ocala, FL, Denver, CO,
This study, for patients who have Stage IIIC colorectal cancer and who underwent
5-fluorouracil/leucovorin with oxaliplatin (FOLFOX) chemotherapy after surgery, will test to
see if regorafenib given after the completion of FOLFOX improves treatment, compared to
standard of care (SOC), which is no further treatment.
Patients with Stage IIIC colon cancer have a 5-year survival rate of 28%. Stage III colon
cancer indicates that lymph nodes are involved.
Adjuvant FOLFOX only reduces the risk of recurrence of colorectal cancer by 40%, so almost
50% of patients still die from the disease. It is estimated that 50% of the patients relapse
within 18 months.
Because the prognosis of colorectal cancer is dependent on disease stage and because
metastatic disease is incurable, the concept of adding regorafenib to adjuvant FOLFOX has
been developed to allow patients with high-risk colorectal cancer the best chance of cure.
It is proposed to treat high-risk colorectal patients (Stage IIIC [T4a, N2a, M0] or
[T3-4a,N2b, M0], or [T4b, N1-N2, M0] per American Joint Committee on Cancer [AJCC] 7th ed.)
selected from the iKnowMed (iKM) electronic health records database who have completed
adjuvant FOLFOX. This feasibility study is to find the starting dose of regorafenib and
estimates that at least 75% of the patients will be able to tolerate the full dose of
regorafenib after receiving adjuvant FOLFOX.
Patients will be randomly assigned to regorafenib or to SOC (no treatment). In order to test
the best tolerated starting dose, the first 50 patients will receive regorafenib and will be
randomized 1:1 to either 120 mg by mouth (PO) or 160 mg PO. If the 120 mg dose is well
tolerated and the toxicities are not severe (Grade 2 or less) upon the completion of cycle
2, the dose will be increased to 160 mg starting with Cycle 3. Registration and
randomization of patients will resume after the 26th then after the 50th patient completes 3
cycles of study treatment. The Data Safety Monitoring Board (DSMB) will meet after the 26th
patient completes 3 cycles of treatment and the second meeting will take place after the
50th patient completes 3 cycles. If needed, a third DSMB meeting will be scheduled. The
remaining 214 patients will be randomized 2:3 to the decided starting dose versus SOC.
In addition, evaluating the Texture (spatial variations in pixel intensity) in computed
tomography (CT) scans might help predict the risk of recurrence. Therefore, CT disks will be
sent to Imaging Endpoints Core Lab, Scottsdale, AZ, where the TexRAD platform (a software
algorithm) will be used for analysis.
- A signed Patient Authorization Form (HIPAA) has been obtained prior to registration
- Subjects must be able to understand and be willing to sign the written informed
consent form. A signed informed consent form must be appropriately obtained prior to
the conduct of any trial-specific procedure.
- Age ≥ 18 years.
- Stage IIIC colorectal cancer (T4a, N2a, M0) or (T3-4a, N2b, M0), or (T4b, N1- N2, M0)
(per AJCC 7th ed).
- Must have started adjuvant FOLFOX chemotherapy within 8 weeks of resection for
- CT scan that demonstrates no evidence of disease (NED) after completion of adjuvant
therapy Note: This CT scan will also be used for Texture analysis.
- Received FOLFOX within 6 weeks before starting regorafenib
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Life expectancy of at least 12 weeks (3 months).
- Complete Metabolic Profile (CMP) within normal limits
- Adequate bone marrow, liver, and renal function as assessed by the following
- Total bilirubin ≤ 1.5 x the upper limits of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x ULN
- Alkaline phosphatase limit ≤ 2.5 x ULN
- Lipase ≤ 1.5 x ULN
- Serum creatinine ≤ 1.5 x ULN
- International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x
ULN. (Subjects who are prophylactically treated with an agent such as warfarin
or heparin will be allowed to participate provided that no prior evidence of
underlying abnormality in coagulation parameters exists. Close monitoring of at
least weekly evaluations will be performed until INR/PTT is stable based on a
measurement that is pre-dose as defined by the local standard of care.
- Platelet count ≥ 100,000 /mm3, hemoglobin (Hb) ≥ 9 g/dL, absolute neutrophil
count (ANC) ≥ 1500/mm3. Blood transfusion to meet the inclusion criteria will
not be allowed.
- Normal carcinoembryonic antigen (CEA) prior to study entry
- Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 according to the Modified Diet
in Renal Disease (MDRD) abbreviated formula.
- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of study drug. Post-menopausal women (defined as no
menses for at least 1 year) and surgically sterilized women are not required to
undergo a pregnancy test. The definition of adequate contraception will be based on
the judgment of the investigator.
- Subjects (men and women) of childbearing potential must agree to use adequate
contraception beginning at the signing of the informed consent form (ICF) until at
least 3 months after the last dose of study drug. The definition of adequate
contraception will be based on the judgment of the principal investigator or a
- Subject must be able to swallow and retain oral medication.
- Discretionary use of growth factors allowed
- Previous assignment to treatment during this study. Subjects permanently withdrawn
from study participation will not be allowed to re-enter study.
- Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm
Hg [NCI-Common Toxicity Criteria for Adverse Effects (CTCAE) v4.03] on repeated
measurement) despite optimal medical management.
- Evidence of remaining tumor
- Has local or distant metastasis
- Previous antiangiogenic treatment
- Abnormal hematological, renal, or liver function
- Impaired pulmonary function
- Evidence of ≥ Grade 2 neuropathy
- Active or clinically significant cardiac disease including:
- Congestive heart failure - New York Heart Association (NYHA) > Class II.
- Active coronary artery disease.
- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers
- Unstable angina (anginal symptoms at rest), new-onset angina within 3 months
before randomization, or myocardial infarction within 6 months before
- Evidence or history of bleeding diathesis or coagulopathy.
- Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of
- Subjects with thrombotic, embolic, venous, or arterial events, such as
cerebrovascular accident (including transient ischemic attacks), deep vein
thrombosis, or pulmonary embolism within 6 months of start of study treatment.
- Subjects with any previously untreated or concurrent cancer that is distinct in
primary site or histology from breast cancer except cervical cancer in-situ, treated
basal cell carcinoma, or superficial bladder tumor. Subjects surviving a cancer that
was curatively treated and without evidence of disease for more than 3 years before
randomization are allowed. All cancer treatments must be completed at least 3 years
prior to study entry (ie, signature date of the informed consent form).
- Patients with phaeochromocytoma.
- Known history of human immunodeficiency virus (HIV) infection or current chronic or
active hepatitis B or C infection requiring treatment with antiviral therapy.
- Ongoing infection > Grade 2 NCI-CTCAE v4.03.
- Presence of a non-healing wound, non-healing ulcer, or bone fracture.
- Dehydration Grade ≥ 1 NCI-CTCAE v4.03.
- Patients with seizure disorder requiring medication.
- Persistent proteinuria ≥ Grade 3 NCI-CTCAE v4.03 (> 3.5 g/24 hrs, measured by urine
protein: creatinine ratio on a random urine sample).
- Interstitial lung disease with ongoing signs and symptoms at the time of informed
- Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version
4.03 Grade 2 dyspnea).
- History of organ allograft (including corneal transplant).
- Known or suspected allergy or hypersensitivity to any of the study drugs, study drug
classes, or excipients of the formulations given during the course of this trial.
- Any malabsorption condition.
- Women who are pregnant or breast-feeding.
- Any condition which, in the investigator's opinion, makes the subject unsuitable for
- Substance abuse, medical, psychological or social conditions that may interfere with
the subject's participation in the study or evaluation of the study results.
- Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
immunotherapy, biologic therapy, or tumor embolization) other than study treatment
(regorafenib, other agents being investigated in combination with regorafenib).
- Prior use of regorafenib.
- Concurrent use of another investigational drug or device therapy (ie, outside of
study treatment) during, or within 4 weeks of trial entry (signing of the informed
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
before start of study medication.
- Therapeutic anticoagulation with Vitamin-K antagonists (eg, warfarin) or with
heparins and heparinoids.
o However, prophylactic anticoagulation as described below is allowed:
- Low dose warfarin (1 mg orally, once daily) with PT-INR ≤ 1.5 x ULN is
permitted. Infrequent bleeding or elevations in PT-INR have been reported in
some subjects taking warfarin while on regorafenib therapy. Therefore, subjects
taking concomitant warfarin should be monitored regularly for changes in PT,
PT-INR, or clinical bleeding episodes.
- Low dose aspirin (≤ 100 mg daily).
- Prophylactic doses of heparin.
- Use of any herbal remedy (eg, St. John's wort [Hypericum perforatum]) Note:
Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors
may be used in the management of acute toxicity, such as febrile neutropenia, when
clinically indicated or at the investigator's discretion. However, they may not be
substituted for a required dose reduction. Subjects are permitted to take chronic