UMIN-CTR Clinical Trial

Basic information
Official scientific title of the study	Randomized Phase II Study of Regorafenib followed by Cetuximab versus Reverse SequenCe for Wild-Type KRAS Metastatic Colorectal Cancer Previously Treated with Fluoropyrimidine, Oxaliplatin, and Irinotecan (REVERECE)
Title of the study (Brief title)	Randomized Phase II Study of Sequential Treatment of Regorafenib and Cetuximab for colorectal cancer (REVERCE)
Region	Japan

Condition
Condition	Colorectal cancer
Classification by specialty	Gastroenterology
Classification by malignancy	Malignancy
Genomic information	NO

Objectives
Narrative objectives1	This is a randomized phase II study designed to evaluate the efficacy and safety of sequential treatment with regorafenib (Treatment 1) followed by cetuximab +/- irinotecan (Treatment 2) (Arm A) for wild-type KRAS metastatic colorectal cancer after treatment failure with or intolerable to chemotherapy including fluoropyrimidine, oxaliplatin, and irinotecan as compared with sequential treatment with cetuximab +/- irinotecan) (Treatment 1) followed by regorafenib (Treatment 2) (Arm B) with exploratory analysis for biomarkers.
Basic objectives2	Safety,Efficacy
Basic objectives -Others
Trial characteristics_1	Exploratory
Trial characteristics_2
Developmental phase	Phase II

Assessment
Primary outcomes	Overall survival
Key secondary outcomes	time to sequential treatment failure (TTF), progression-free survival (PFS) of sequential therapy, PFS of Treatment 1 and Treatment 2, response rate of Treatments 1 and Treatment 2, disease control rate of Treatments 1 and Treatment 2, incidence of adverse events , pateints reported outcome of QOL

Base
Study type	Interventional

Study design
Basic design	Parallel
Randomization	Randomized
Randomization unit	Individual
Blinding	Open -no one is blinded
Control	Active
Stratification	NO
Dynamic allocation	YES
Institution consideration	Institution is considered as adjustment factor in dynamic allocation.
Blocking	NO
Concealment	Central registration

Intervention
No. of arms	2
Purpose of intervention	Treatment
Type of intervention	Medicine
Interventions/Control_1	sequential treatment with regorafenib followed by cetuximab +/- irinotecan
Interventions/Control_2	sequential treatment with cetuximab +/- irinotecan followed by regorafenib
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	90 years-old >=
Gender	Male and Female
Key inclusion criteria	1)Histologically proven, unresectable distant metastatic or locally advanced colorectal adenocarcinoma 2)No KRAS mutation (codon 12 & 13) (i,e, wild-type KRAS): KRAS test will be performed at the study site or an external institution using an appropriate technique such as direct-sequence, Scorpions and ARMS, TaqMan Mutation Detection Assays or Luminex. 3)-5)PD or intolerable to chemotherapy including fluoropyrimidine*, L-OHP* and CPT-11 * * Disease progression or intolerable to chemotherapy are defined as those who meet any of the following: i)Radiographically confirmed recurrence during or within 6 months after adjuvant therapy ii)Radiographically or clinically confirmed disease progression during or within 3 months after chemotherapy for advanced cancer iii)Unacceptable toxicity precluding resumption of treatment 6) Evaluable lesion(s) a) Measurable lesion(s) is not mandatory b) Excluding patients with only body cavity fluid, bone metastasis, skin metastasis, pulmonary lymphangiosis, radiographically undetectable abdominal mass, or cystic lesion 7)>= 20 years at the time of informed consent 8)ECOG PS: 0-1 9)Adequate organ functions within 7 days before enrollment (excluding blood transfusion or hematopoietic factor preparations such as G-CSF within 14 days before enrollment) -Neutrophil count: >= 1500/mm3 -Hb: >=8.0 g/dL (blood transfusion more than 2 weeks before is allowed) -Plt count:>7.5 x 104/mm3 -AST, ALT: <= ULN x 2.5 <= ULN x 5 in patients with liver metastasis) -Total bilirubin: <= ULN x 1.5 -Creatinine: <= 1.5 mg/dL -Protein urine i) Protein urine (urine dipstick) <= 2+ or ii) UPC ratio <3.5 or iii)24-hour protein urine <= 3500 mg -PT-INR: <= ULN x 1.5 (<= x3in the subjects with anticoagulants) 10)Expected to survive for at least 60 days after entry 11)At least 2 weeks of washout from previous radiotherapy and/or chemotherapy for the underlying disease 12)Written consent after detailed explanation of the study before entry including consent for QOL and BMs
Key exclusion criteria	1)Previous treatment with regorafenib, anti-EGFR antibody (cetuximab/panitumumab) or participation in clinical trial for regorafenib 2)Poorly controlled hypertension (SBP>150 mmHg or DBP >90 mmHg despite appropriate treatment) 3)Unstable angina, myocardial infarction, brain infarction, or pulmonary embolism within 6 months before entry 4)Body cavity fluid (e.g., pleural effusion, ascites, pericardial fluid) requiring intervention 5)Local or systemic active infection (grade 3 or higher according to the CTCAE ver. 4) requiring intervention 6)Symptomatic brain metastasis or brain metastasis requiring regular medication (e.g., mannitol, steroids, antiepileptic drugs) 7)Intestinal paralysis or severe gastrointestinal obstruction 8)Patients unable to swallow oral medications 9)Grade 3 or higher hemorrhage within 4 weeks before entry 10)History or clear evidence in CT scanof extensive interstitial pulmonary disease (e.g., interstitial pneumonia, pulmonary fibrosis) 11)Heart failure &#8805; NYHA II 12)History of meningitis carcinomatosis, uncontrollable seizures (status epilepticus, intractable epilepsy), clinically significant mental disorder, or central nerve disorder 13)Active hepatitis B or C 14)Other active malignancies that may affect the prognosis 15)Pregnant or possibly pregnant women, lactating women, or patients unwilling to use adequate contraception 16)Uncontrolled diarrhea (diarrhea interfering with daily life despite appropriate treatment) 17)Unhealed wound (excluding central venous port), ulcer, or bone fracture 18)Any major surgery. open biopsy or traumatic injury within 28 days before enrollment (excluding the same day of the week 4 weeks ago) or colostomy without intestinal resection within 14 days before enrollment 19)Daily systemic steroid treatment (for such as collagen disease) 20)Known hypersensitivity to study drugs, study drug classes, or excipients in the formulation 21)Patients who, in the opinion of the investigator, are inappropriate for the study
Target sample size	180

Research contact person
Name of lead principal investigator	Takayuki Yoshino
Organization	National Cancer Center Hospital East
Division name	Department of Gastroenterology and Gastrointestinal Oncology
Address	6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577 Japan
TEL	04-7133-1111
Email	kshitara@east.ncc.go.jp

Public contact
Name of contact person	Kohei Shitara
Organization	National Cancer Center Hospital East
Division name	Department of Gastroenterology and Gastrointestinal Oncology
Address	6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577 Japan
TEL	04-7133-1111
Homepage URL
Email	kshitara@east.ncc.go.jp

Sponsor
Institute	REVERCE study group
Institute
Department

Funding Source
Organization	Bayer Yahin Ltd.
Organization
Division
Category of Funding Organization	Profit organization
Nationality of Funding Organization	Japan

Other related organizations
Co-sponsor
Name of secondary funｄer(s)

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions	REVERCE参加施設

Other administrative information
Date of disclosure of the study information	2013 Year 09 Month 30 Day

Progress
Recruitment status	No longer recruiting
Date of protocol fixation	2013 Year 07 Month 25 Day
Anticipated trial start date	2013 Year 11 Month 15 Day
Last follow-up date	2017 Year 08 Month 07 Day
Date of closure to data entry	2017 Year 09 Month 10 Day
Date trial data considered complete	2017 Year 09 Month 10 Day
Date analysis concluded

Related information
URL releasing protocol
Publication of results	Unpublished
URL releasing results
Results
Other related information

Management information
Registered date	2013 Year 07 Month 26 Day
Last modified on	2017 Year 09 Month 19 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013232