Achievement of Improved Survival by Molecular Targeted Chemotherapy and Liver Resection for Not Optimally Resectable Colorectal Liver Metastases (ATOM)

Randomized Phase II Study of mFOLFOX6 + Bevacizumab or mFOLFOX6 + Cetuximab in Liver Only Metastasis From KRAS Wild Type Colorectal Cancer

The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Liver Only Metastasis From KRAS Exon 2 Wild Type (Under Protocol 1.0-1.2 Edition) and RAS Wild Type (Under Protocol 2.0 Edition) Colorectal Cancer
• Intervention / Treatment: Drug: Bevacizumab; Drug: L-OHP; Drug: l-LV; Drug: 5-FU; Drug: 5-FU; Drug: Cetuximab

Detailed Description

Description: The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Tokyo
    • Shinjuku-ku, Tokyo, Japan, 162-0814
      • EPS Corporation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histopathologically confirmed colorectal cancer (adenocarcinoma) excluding vermiform appendix cancer and proctos cancer.
2. RAS wild type

3. Synchronous* or metachronous liver limited meitastasis with no extrahepatic desiease

   • shychronous liver limited metastasis with primary lesion less than two thirds of the circumference
   • patients with primary lesion more than two thirds of the circumference can be enrolled after primary resection
4. Patients who has one or more lesion(s) of diameter 1 cm or larger (RECEST v1.1) be able to assess continuously on the basis of the protocol by contrast enhanced CT or contrast enhanced MRI of the liver:

(1)Liver metastases 5 or more (2)Liver metastases with 5 cm or larger in greatest dimension (3)Unresectable considering remaining hepatic function (4)Invasion into all hepatic veins or inferior vena cava (5)Invasion into both right and left hepatic arteries or portal veins 5.No prior chemotherapy for colorectal cancer including hepatic arterial infusion. Excluding postoperative and preoperative chemoradiotherapy except for rectal cancer with synchronous liver metastases. Patients received postoperative chemotherapy containing oxaliplatin have to be enrolled after 24 weeks from the last oxaliplatin administration.

6.No previous treatment including ablation therapy, cryotherapy and chemotherapy for metastases 7.Age at enrollment is >=20 and =<80 years 8.The Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 9.Life expectancy from the day of enrollment is 3 months or longer 10.Major organ functions less than 14 days prior to entry meet the following criteria.

1. Neu >= 1500/mm3
2. Pt >= 10.0x10^4/mm3
3. Hb >= 9.0 g/dL
4. T-bil =< 2.0 mg/dL
5. AST and ALT =< 200 IU/L
6. sCr =< 1.20 mg/dL
7. INR < 1.5
8. Proteinuria =< 2+ 11.Written informed consent

Exclusion Criteria:

1. Previously experienced severe allergic reaction to drugs
2. Receiving anti-platelet drugs (aspirin >= 325 mg/day) or NSAIDs
3. Receiving chronic systemic corticosteroid treatment
4. Surgery/ biopsy with skin incision or traumatic injury with suture less than 14 days prior to entry. Excluding, suture for implanted venous reservoirs with catherter is allowed.
5. Severe postoperative complications (e.g. postoperative infection, anastomic dehiscence or paralytic ileus)
6. Diagnosed as hereditary colorectal cancer
7. Active other malignancies
8. Cerebrovascular disease or symptoms less than 1 year prior to entry
9. Pleural effusion, ascites or cardiac effusion requiring drainage
10. Hemorrhage/bleeding, paralytic ileus, obstruction or ulceration of gastrointestinal tract
11. Perforation of gastrointestinal tract less than 1 year prior to entry
12. Presence of active infection
13. HBs antigen or HCV antibody positive
14. Uncontrolled comorbidity including hypertension, diabetes, arrhythmia, or other diseases (such as cardiac disorder, interstitial pneumonia or renal disorder)
15. Presence of >= grade 2 diarrhea
16. Presence of >= grade 1 peripheral neuropathy
17. Pregnant or lactating women. Women and men with childbearing potential unwilling to use effective means of contraception
18. Psychosis or psychiatric symptoms who are not able to comply with the protocol
19. Any other medical conditions disable to comply with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mFOLFOX + Bmab; mFOLFOX plus bevacizumab	Drug: Bevacizumab; 5 mg/kg intravenously administered over 90 minutes (can be reduced to 30 minutes at the minimum) on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Avastin; Drug: L-OHP; 85 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Oxaliplatin; Drug: l-LV; 200 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Levofolinate; Drug: 5-FU; 400 mg/m2 intravenous bolus on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Fluorouracil; Drug: 5-FU; 2400 mg/m2 continuous infusion over 46 hours on day 1 and 2 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Fluorouracil
Active Comparator: mFOLFOX + Cmab; mFOLFOX plus cetuximab	Drug: L-OHP; 85 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Oxaliplatin; Drug: l-LV; 200 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Levofolinate; Drug: 5-FU; 400 mg/m2 intravenous bolus on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Fluorouracil; Drug: 5-FU; 2400 mg/m2 continuous infusion over 46 hours on day 1 and 2 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Fluorouracil; Drug: Cetuximab; 250 mg/m2 intravenously administered over 60 minutes (400 mg/m2 over 120 minutes as the initial dose) on day 1 and day 8 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.; Other Names: Erbitux

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	assessed by Independent Review Committee	assessed every 8 weeks, up to 4 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Response rate	assessed every 8 weeks, up to 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor shrinkage rate at 8 week		assessed at 8 week, up to 8 weeks
Liver resection rate		assessed every 8 weeks, up to 4 years
R0 liver resection rate	pathologically confirmed R0 liver resection rate	assessed every 8 weeks, up to 4 years
Progression-free survival	assessed by investigators	assessed every 8 weeks, up to 4 years
Time to treatment-failure		assessed every 2 weeks, up to 4 years
Overall survival		assessed every 2 weeks, up to 4 years
Quality of life		assessed every 16 weeks, up to 1 year
Incidence of adverse events		assessed every 2 weeks, up to 4 years
Progression-free survival among the RAS wild type subpopulation	All the assessment is repeated for a maximum of 4 years.	assessed every 8 weeks, up to 4 years

Collaborators and Investigators

• Sponsor: EPS Corporation
• Investigators: Principal Investigator: Yoshihiko Maehara, MD,PhD,FACS, Graduate School of Medical Science, Kyushu University, Department of Surgery and Science; Principal Investigator: Naohiro Tomita, MD, PhD, Hyogo College of Medicine, Department of Surgery; Principal Investigator: Ichinosuke Hyodo, MD, PhD, Tsukuba University, Graduate School of Medicine; Principal Investigator: Michiaki Unno, MD, PhD, Tohoku University, Division of Gastroenterological Surgery

Publications and helpful links

General Publications

• Oki E, Emi Y, Yamanaka T, Uetake H, Muro K, Takahashi T, Nagasaka T, Hatano E, Ojima H, Manaka D, Kusumoto T, Katayose Y, Fujiwara T, Yoshida K, Unno M, Hyodo I, Tomita N, Sugihara K, Maehara Y. Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial). Br J Cancer. 2019 Jul;121(3):222-229. doi: 10.1038/s41416-019-0518-2. Epub 2019 Jul 9.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: April 14, 2013
• First Submitted That Met QC Criteria: April 19, 2013
• First Posted (Estimate): April 22, 2013

Study Record Updates

• Last Update Posted (Actual): August 2, 2017
• Last Update Submitted That Met QC Criteria: August 1, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Bevacizumab; liver metastasis; Cetuximab; KRAS wild type colorectal cancer; RAS wild type colorectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Fluorouracil; Oxaliplatin; Bevacizumab; Cetuximab
• Other Study ID Numbers: ATOM (Radius Health, Inc.); UMIN000010209 (Other Identifier: UMIN)