Oral Steroids for Regorafenib-induced Fatigue/Malaise in Unresectable mCRC (KSCC1402/HGCSG1402)

The objective of this randomized placebo-controlled Phase 2 study is to evaluate prophylactic effects of dexamethasone for fatigue and malaise (weakness, lethargy, malaise) resulting from regorafenib treatment, as well as to assess treatment continuation of regorafenib.

1. Patient registration procedure

   If it is confirmed that the subject meets the inclusion criteria and correspondent none of the exclusion criteria, the subject is registered by using Clinical Research Support Center (CReS) Kyushu registration/allocation system. The registration with the registration/allocation system is available for 24 hr (URL: https://reg.cres-kyushu.or.jp/qmin/login/) and needs for individual identifier (ID) and password.
2. Quality management

   * Preparation and management of the test drugs

The test drugs are an active drug, which is a capsule filled with dexamethasone powder and lactose, and a placebo, which is a capsule filled with only lactose. The test drugs will be prepared by the Department of Pharmacy (manager: Professor Masuda), Kyushu University Hospital in accordance with the procedures for preparation of the test drugs. Dexamethasone powder and lactose will be purchased by Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University from Tomita Pharmaceutical and delivered to the pharmacy department. Research funds will be used for the purchase. The capsule will be purchased from Tomita Pharmaceutical. The test drugs will be delivered to CReS-Kyushu (enrollment/data center) and managed using a double-blind method in accordance with the procedures. The double-blind code will be kept by the person responsible for management of the test drugs Shoji Tokunaga, Medical Information Center, Kyushu University, and a backup of the code will be kept by Hidekazu Aratani of CReS-Kyushu.

The test drugs will be managed according to the investigational drug number and stored at the warehouse of the Fukuoka branch of Yamato Logistics Co., Ltd. The warehouse is certified to store drugs for humans for more than 2 years under the supervision of pharmacists.

In the participating medical institution, manager and vice manager for the management of the test drugs will be appointed. It is preferable that the manager and vice managers are selected from among personnel who are experienced in drug management including personnel from the Department of Pharmacy or clinical trial management office. The manager is not allowed to become the investigator or sub-investigator. A physician who may treat subjects is not allowed to become the manager.

The electronic data capture (EDC) system will be used for communications between the enrollment/data center, Yamato Logistics and participating medical institution. Information on subjects will be reported by e-mail to the data center, and the data center will ensure the information by telephone to Yamato Logistics and the investigational drug management division of the medical institution. The test drugs will be delivered by Yamato Logistics to the medical institution. The test drugs for only a subject will be delivered once (allocation adjustment factor). Considering that a number of days are necessary for delivery, there should be at least 3 working days between enrollment and start of treatment. The interval between enrollment and start of treatments should be up to 14 days. Physicians treating subjects are not allowed to manage the test drugs. The vice manager will manage the test drugs according to subjects under the supervision of the manager. Orders for the test drugs will be made by letter or e-mail in accordance with the medical institution's procedures. A sufficient number of capsules of the test drugs until the next hospital visit will be ordered/prescribed once. If the test drugs are used properly in accordance with the protocol, an order/prescription for the test drugs will be made every 7 days. Subjects (patients) will be advised to keep records of the use of regorafenib and test drugs in the medication diary. The remaining number of capsules of the test drugs will be checked in consideration of the use of the test drugs. The remaining test drugs will be returned to the study office. In accordance with the protocol, the test drugs should be prescribed for 28-day treatment, but will be prescribed for 30-day treatment considering loss and damage. The test drug for 2-day treatment should be left unused when treatment is completed. The remaining test drugs will be returned to the enrollment/data center.

When the test drugs are delivered, the enrollment number, investigational drug number, reception date, the number of capsules of the test drugs delivered will be entered in the EDC system. Also, the number of capsules prescribed, date of prescription, remaining number of capsules (total number of capsules stored including the number of capsules returned), confirmation date of completion/discontinuation of the protocol treatment, total remaining number of capsules including the number of capsules returned will be entered in the EDC system.

The number of capsules lost and reasons for the loss will be entered in the EDC system.

* Monitoring

A central monitoring or in-site monitoring are carried out based on the data from case report form (CRF) collecting at data coordinating center. In principle, an on-site monitoring is not carried out, but it may be carried out when the on-site monitoring is determined to need by Kyushu Study group of Clinical Cancer (KSCC) steering committee from the results of the central monitoring so on.

Data Monitoring Committee A Data Monitoring Committee (DMC) has been established.

* Data entry

all data will be entered by the double entry method. Referential data rules, valid values, range checks, and consistency checks against data already stored in the database will be supported. Checks will be applied at the time of data entry into a specific field. Additional errors will be detected by programs designed to detect missing data or specific errors in the data. The investigator who receives the inquiry will respond by checking the original forms for inconsistency, checking other sources to determine the correction, modifying the original paper form entering a response to the query.

* Regular monitoring report

A regular monitoring report generated by data coordinating center is submitted to KSCC Steering Committee, principal investigator, the DMC etc and it is reviewed according to "KSCC regulation on the monitoring". The information on the status of site ethics committee (EC) approval and the achievement of enrollment: number of enrollment- total/per periodical, total/per site, is reported monthly using e-mail.

* Contents of monitoring report

Study abstract: schema/purpose/subject/endpoint/definition of treatment/anticipated enrollment number/progress of the study Enrollment status: per participating site/total Monitoring activity: contents of activity/CRF collection per site/uncollected CRF, inquiry Review of the eligible treatment case：the case of ineligible possibility/the case determined as ineligible/number of eligible case/the case determined as non-treatment/total number of treatment case Review of a target population for analysis: the number of cases targeted for efficacy analysis/safety analysis Patient background Treatment time-course: summary of on-treatment and discontinuation/summary of reason for discontinuation/list of reason for discontinuation Protocol violation/deviation Safety evaluation: serious adverse reaction, event/the case which was notified to the study group among the adverse reactions, events with an ordinary report/general adverse events Others

* Audit

A site audit is carried out by the audit members of KSCC Coordinating Center, data coordinating center, medical staff of other site under the approval of the site director according to "KSCC regulation for site audit". The results of the audit are reported to the site director, KSCC Steering Committee, principal investigator etc. (if required, to DMC).

Eligibility Criteria:
Inclusion Criteria:

* Capable of granting informed consent in writing for receiving treatment outlined in this protocol
* The investigators determines that the patient can receive the treatment outlined in this protocol
* Histological diagnosis of adenocarcinoma of either the colon or the rectum, regardless of RAS mutation
* Metastatic colorectal cancer scheduled for treatment with regorafenib
* Lesions are either measurable or non-measurable according to RECIST ver. 1.1
* Contrasted torso CT within 28 days before enrollment
* At least 20 years of age
* PS 0-1
* Bone marrow, hepatic, and renal functions have all been confirmed as normal within 14 days prior to initiation of regorafenib treatment
* Life expectancy of at least 3 months

Exclusion Criteria:

* Used regorafenib previously
* Blood transfusion or granulocyte-colony stimulating factor (G-CSF) administration within 14 days
* Grade 2 or higher fatigue or malaise or asthenia according to NCI-CTCAE ver. 4.0
* History of a different type of cancer according to histological findings or cancer of a different primary focus within the past 5 years. The following are excluded: carcinoma in situ of the cervix, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis, and T1), gastric cancer,non-invasive breast cancer, etc
* Highly invasive surgery, an open biopsy, or who have received significant trauma within 28 days of initiating regorafenib treatment
* Congestive cardiac failure of New York Heart Association (NYHA) \>=Class 2
* Unstable angina (symptoms at rest),new-onset angina (onset within past 3 months), or a history of myocardial infarction within 6 months of initiating treatment
* Arrhythmia requiring treatment with anti-arrhythmia drugs
* Uncontrollable hypertension
* Pleural effusion or ascites causing dyspnea (NCI-CTCAE \>=Grade 2)
* History of venous or arterial thrombosis or embolism within 6 months prior to initiation of treatment, including cerebrovascular accidents, deep vein thrombosis, or pulmonary embolism
* Patients with active infections of NCI-CTCAE \>=Grade 3
* Positive for either hepatitis B (HB)s antigen or hepatitis C virus (HCV) antibody
* Seizure disorders requiring drug treatment
* Cerebral metastases or history of such
* History of organ transplant
* Symptoms or history of hemorrhagic tendency, regardless of severity
* Some form of hemorrhaging (NCI-CTCAE \>=Grade 2) within 4 weeks prior to initiating treatment
* Incurable wound, fracture or ulcer
* Renal failure requiring either hemodialysis or peritoneal dialysis
* Dehydration symptoms of NCI-CTCAE \>=Grade 1
* Abusing drugs or who are in a physical, psychological, or social state which might impair study participation or evaluation of results
* Interstitial lung disease with active signs or symptoms
* Have difficulty taking oral drugs
* Digestion absorption disorders
* Adverse events resulting from previous treatments or procedures which have not yet resolved (NCI-CTCAE \>=Grade 2)
* Received systemic anti-cancer treatments within 2 weeks prior to initiation of regorafenib treatment, including chemotherapy, molecular target drugs, immunotherapy, or hormone therapy
* Poorly controlled glucose tolerance abnormalities due to diabetes mellitus (patients using insulin)
* Active GI ulcers or a history of such
* Glaucoma
* Oral steroids are otherwise contraindicated
* Either pregnant or nursing. Women who may become pregnant must have a negative pregnancy test within 7 days prior to initiating treatment
* Women who may become pregnant, or men whose partners may become pregnant, must agree to use appropriate contraceptives from granting of consent to 3 months after conclusion of regorafenib therapy
* Other illnesses or conditions which, according to the judgment of the investigator, may result in physical harm caused by the study, or which may impair study compliance