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Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer

Information source: Academic and Community Cancer Research United
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Colon Adenocarcinoma; Fatigue; Palmar-Plantar Erythodysthesia; Rectal Adenocarcinoma; Recurrent Colon Carcinoma; Recurrent Rectal Carcinoma; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

Intervention: Regorafenib (Drug); Clobetasol Propionate (Drug); Pharmacological Study (Other); Quality-of-Life Assessment (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: Academic and Community Cancer Research United

Official(s) and/or principal investigator(s):
Tanios Bekaii-Saab, Principal Investigator, Affiliation: Academic and Community Cancer Research United


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.

Clinical Details

Official title: Regorafenib Dose Optimization Study (ReDOS): A Phase II Randomized Study of Lower Dose Regorafenib Compared to Standard Dose Regorafenib in Patients With Refractory Metastatic Colorectal Cancer (mCRC)

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Proportion of patients in each arm who complete 2 courses of treatment and who intend to initiate course 3 if no progression is noted on the planned disease evaluation

Secondary outcome:




Cumulative (total) dose of regorafenib received by patients in the first two courses

Proportion of patients overall and within each arm experiencing grade 3 or 4 HFS or fatigue

Changes in QOL (according to the HFS14 questionnaire)

Changes in QOL (according to the LASA questionnaire)

Detailed description: PRIMARY OBJECTIVES: I. Evaluate the proportion of patients in each arm who complete 2 cycles of treatment and who intend to initiate cycle 3 if no progression is noted on the planned 8-week scan. SECONDARY OBJECTIVES: I. Evaluate outcome measures for efficacy in each arm including progression free survival (PFS), time to progression (TTP), time to failure (TTF) and overall survival (OS). II. Compare between arms the cumulative dose received within the first two cycles. III. Evaluate the proportion of patients in each arm that exhibit grade 3 palmar-plantar erythrodysesthesia syndrome (PPES) and/or fatigue, and make comparisons between regorafenib dosing strategies and pre-emptive vs. reactive strategies to address PPES. IV. Compare quality of life (QOL) between treatment arms (regorafenib dosing strategies and preemptive vs. reactive PPES strategies) as measured by the Hand and Foot Syndrome (HFS)14, Brief Fatigue Inventory (BFI), and Linear Analogue Self-Assessment (LASA) questionnaires. V. Compare need for topical or oral (PO) analgesia between treatment arms (regorafenib dosing strategies and pre-emptive vs. reactive PPES strategies). TERTIARY OBJECTIVES: I. Evaluate and compare trough (Cmin) pharmacokinetics (PK) during the first 2 treatment cycles for regorafenib and active metabolites M2, M5 between the low dose (dose escalation) and the standard dose cohorts, and correlate with toxicity profile. II. Evaluate the correlation between PK parameters and tumor response/stable disease after the first two cycles. III. Evaluate the correlation between PK parameters and PFS and OS. IV. Evaluate if trough

(minimum [Cmin]) concentrations are associated with patient-specific factors (such as - but

not limited to - age and concomitant medications).

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


- 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


- 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

Locations and Contacts

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

Additional Information

Starting date: March 2015
Last updated: July 22, 2015

Page last updated: August 23, 2015

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