Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

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

Protocol: OSU-15088

Full 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)


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.

Study Objective


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.


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).


I. Evaluate and compare trough minimum concentration (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 (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.

Are you eligible?

Inclusion Criteria:

Histological or cytological documentation of adenocarcinoma of the colon or rectum

Advanced or metastatic colorectal cancer with no curative options available and progression on previous standard therapy, including an EGFR inhibitor if KRAS wild-type

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 and banking 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: Pace makers, 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])

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 g/dl

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 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 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 for cancers that were distinct in a primary site other than colorectal 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 =< 4 weeks from registration (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib, other agents being investigated in combination with regorafenib)

Current use of clobetasol propionate

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

Colon Cancer Rectal Cancer Gastrointestinal Cancers