This randomized phase II trial studies how well lower-dose compared to standard dose
regorafenib works in treating patients with colorectal cancer that has spread from the
primary site (place where it started) to other places in the body and does not respond to
treatment. Regorafenib may stop the growth of colorectal cancer by blocking the growth of
new blood vessels necessary for tumor growth and by blocking some of the enzymes needed for
cell growth. It is not yet known whether lower-dose or standard dose regorafenib is more
effective in treating patients with colorectal cancer. Clobetasol propionate is a steroid
cream that is commonly used to treat a variety of skin conditions and may help prevent
hand-foot skin reactions in patients receiving regorafenib.
(minimum [Cmin]) concentrations are associated with patient-specific factors (such as - but
OUTLINE: Patients are randomized to 1 of 4 treatment arms.
ARM A1: Patients receive lower-dose regorafenib PO once daily (QD) on days 1-21 and
pre-emptive clobetasol propionate given topically twice daily (BID) for 12 weeks, beginning
on day 1 of regorafenib.
ARM A2: Patients receive lower-dose regorafenib PO as in Arm A1 and reactive clobetasol
propionate given topically BID beginning on day 1 per physician discretion upon occurrence
of PPES grade >= 1.
ARM B1: Patients receive standard dose regorafenib PO QD on days 1-21 and pre-emptive
clobetasol propionate as in Arm A1.
ARM B2: Patients receive standard dose regorafenib PO as in Arm B1 and reactive clobetasol
propionate as in Arm A2.
In all arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up for 2-6 months.
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Inclusion Criteria:
- Histological or cytological documentation of adenocarcinoma of the colon or rectum
- Measurable or non-measurable disease
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Life expectancy of >= 3 months
- Absolute neutrophil count (ANC) > 1500/mm^3
- Platelet count > 100,000/mm^3
- Hemoglobin > 9. 0 g/dL
- Total bilirubin =< 1. 5 x upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2. 5 x ULN (=<
5 x ULN for subjects with liver involvement of their cancer)
- Serum creatinine =< 1. 5 x ULN
- International normalized ratio (INR)/partial thromboplastin time (PTT) =< 1. 5 x ULN
- NOTE: patients who are therapeutically 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
- Alkaline phosphatase limit =< 2. 5 x ULN (=< 5 x ULN for patients with liver
involvement of their cancer)
- Negative serum pregnancy test done =< 7 days prior to randomization, for women of
childbearing potential only; note: 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
- Ability to complete questionnaire(s) by themselves or with assistance
- Provide informed written consent
- Willing to return to enrolling institution for follow-up (during the active
monitoring phase of the study)
- Willing to provide blood samples for correlative research purposes
Exclusion Criteria:
- Prior treatment with regorafenib
- Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days
prior to randomization
- Congestive heart failure > New York Heart Association (NYHA) class 2
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
months) or myocardial infarction less than 6 months prior to randomization
- Cardiac arrhythmias requiring anti-arrhythmic therapy; note: beta blockers or digoxin
are permitted
- Uncontrolled hypertension; (systolic blood pressure > 140 mmHg or diastolic pressure
> 90 mmHg despite optimal medical management)
- History of or current pheochromocytoma
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism =<
6 months prior to randomization
- Ongoing infection > grade 2 National Cancer Institute (NCI)-Common Terminology
Criteria for Adverse Events (CTCAE) version 4. 0
- Known history of chronic hepatitis B or C
- Patients with seizure disorder requiring medication
- Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months
from definitive therapy, has a negative imaging study within 4 weeks of randomization
and is clinically stable with respect to the tumor at the time of randomization;
note: patient must not be undergoing acute steroid therapy or taper (chronic steroid
therapy is acceptable provided that the dose is stable for one month prior to and
following screening radiographic studies)
- History of organ allograft (including corneal transplant)
- Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE
grade 3 =< 4 weeks prior to randomization
- Non-healing wound, ulcer, or bone fracture
- Renal failure requiring hematological (hemo-) or peritoneal dialysis
- Dehydration CTCAE (version 4. 0) grade >= 1
- Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients
in the formulation
- Interstitial lung disease with ongoing signs and symptoms at the time of informed
consent
- Persistent proteinuria of Common Toxicity Criteria (CTC) grade 3 or higher (> 3. 5
g/24 hours [hrs], measured by urine protein: creatinine ratio on a random urine
sample)
- Patients unable to swallow oral medications
- Any malabsorption condition
- Unresolved toxicity greater than CTCAE (version 4. 0) grade 1 attributed to any prior
therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity =< grade 2
- Albumin levels > 2. 5
- Any of the following:
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate
contraception
- NOTE: 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 2 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 designated associate
- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens
- Immunocompromised patients and patients known to be human immunodeficiency virus
(HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known
to be HIV positive, but without clinical evidence of an immunocompromised state, are
eligible for this trial
- Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm
- Previous or concurrent cancer that is distinct in primary site or histology from
colorectal cancer within 3 years prior to randomization EXCEPT for curatively treated
cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta
[non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]);
note: all cancer treatments must be completed at least 3 years prior to randomization
(i. e., signature date of the informed consent form)
- Pleural effusion or ascites that causes respiratory compromise (>= CTCAE version 4. 0
grade 2 dyspnea)
- 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)
- Therapeutic anticoagulation with vitamin-K antagonists (e. g., warfarin) or with
heparins and heparinoids; note: however, prophylactic anticoagulation as described
below is allowed:
- Low dose warfarin (1 mg orally, once daily) with INR/PTT =< 1. 5 x ULN is
permitted; infrequent bleeding or elevations in INR/PTT have been reported in
some subjects taking warfarin while on regorafenib therapy; therefore, subjects
taking concomitant warfarin should be monitored regularly for changes in INR/PTT
or clinical bleeding episodes
- Low dose aspirin (=< 100 mg daily)
- Prophylactic doses of heparin
- Use of any herbal remedy (e. g. St. John's Wort [Hypericum perforatum])
- Patients unable to ambulate or who have amputations or paralysis of any extremity
- History of contact dermatitis to clobetasol propionate or similarly fluorinated
steroids or other steroids with the propionate ester
Illinois Cancer Care, PC, Peoria, Illinois 61615, United States; Recruiting
Ashton Hitchcock, BA, Phone: 309-243-3000, Email: ahitchcock@illinoiscancercare.com
Madhuri Bajaj, MD, Principal Investigator
Northern Indiana Cancer Research Consortium, South Bend, Indiana 46628, United States; Recruiting
Lisa Barnaby, Phone: 574-231-6484
Siouxland Regional Cancer Center, Sioux City, Iowa 51101, United States; Recruiting
Thomas Hoopingarner, Phone: 712-252-9326, Email: hoopingarnert@jencc.com
Donal Wender, M.D., Principal Investigator
Mayo Clinic, Rochester, Minnesota 55905, United States; Not yet recruiting
Clinical Trials Referral Office, Phone: 855-776-0015
Jeff A. Sloan, Principal Investigator
Metro-Minnesota CCOP, Saint Louis Park, Minnesota 55416, United States; Recruiting
Daniel Anderson, M.D., Email: elizabeth.wagner@parknicollet.com
Missouri Valley Cancer Consortium CCOP, Omaha, Nebraska 68106, United States; Recruiting
Erin Smith, Phone: 402-991-8070, Ext: 201, Email: esmith@mvcc.cc
Gamini Soori, M.D., Principal Investigator
Hematology Oncology Associates of Central New York PC, East Syracuse, New York 13057, United States; Recruiting
Kelly Cohn, Phone: 315-472-7504
Jeffrey J. Kirshner, M.D., Principal Investigator
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Not yet recruiting
Mario E. Lacouture, Phone: 212-639-7202, Email: lacoutum@mskcc.org
Mario E. Lacouture, Principal Investigator
Ohio State University, Columbus, Ohio 43210, United States; Not yet recruiting
Tanios S. Bekaii-Saab, Phone: 507-538-3555, Email: Tanios.Saab@osumc.edu
Tanios S. Bekaii-Saab, Principal Investigator
University of Washington Medical Center, Seattle, Washington 98195, United States; Not yet recruiting
Elena G. Chiorean, Phone: 800-804-8824, Email: gchiorea@uw.edu
Elena G. Chiorean, Principal Investigator
St. Vincent Regional Cancer Center, Green Bay, Wisconsin 54301, United States; Recruiting
Anthony Jaslowski, M.D., Phone: 920-884-3135, Email: tjaslowski@gboncology.com
Anthony Jaslowski, M.D., Principal Investigator