A Study to Compare the Efficacy of Arfolitixorin Versus Leucovorin in Combination With 5 Fluorouracil, Oxaliplatin, and Bevacizumab in Patients With Advanced Colorectal Cancer

NCT ID: NCT03750786

Last Updated: 2023-10-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 490 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-18
• Study Completion Date: 2022-11-18

Brief Summary

This is a multicenter, randomized, parallel-group, Phase III study in at least 440 patients with advanced colorectal cancer to compare the efficacy of treatment with arfolitixorin versus Leucovorin in combination with 5-fluorouracil, oxaliplatin, and bevacizumab according to modified FOLFOX-6 until PD according to RECIST 1.1 criteria.

Conditions

Colo-rectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group A

ARFOX (Arfolitixorin and 5-FU and Oxaliplatin) and Bevacizumab

Group Type: EXPERIMENTAL

Arfolitixorin

Intervention Type: DRUG

Bevacizumab 5 mg/kg intravenous infusion; Oxaliplatin 85 mg/m2 intravenous infusion; 5-FU 400 mg/m2 intravenous bolus; Arfolitixorin 60 mg/m2 intravenous bolus; 5-FU 2400 mg/m2 intravenous infusion; Arfolitixorin 60 mg/m2 intravenous bolus

Group B

mFOLFOX-6 (Leucovorin and 5-FU and Oxaliplatin) and Bevacizumab

Group Type: ACTIVE_COMPARATOR

Leucovorin

Intervention Type: DRUG

Bevacizumab 5 mg/kg intravenous infusion; Oxaliplatin 85 mg/m2 intravenous infusion; Leucovorin 400 mg/m2 intravenous infusion; 5-FU 400 mg/m2 intravenous infusion; 5-FU 2400 mg/m2 intravenous infusion

Interventions

Arfolitixorin

Bevacizumab 5 mg/kg intravenous infusion; Oxaliplatin 85 mg/m2 intravenous infusion; 5-FU 400 mg/m2 intravenous bolus; Arfolitixorin 60 mg/m2 intravenous bolus; 5-FU 2400 mg/m2 intravenous infusion; Arfolitixorin 60 mg/m2 intravenous bolus

Intervention Type: DRUG

Leucovorin

Bevacizumab 5 mg/kg intravenous infusion; Oxaliplatin 85 mg/m2 intravenous infusion; Leucovorin 400 mg/m2 intravenous infusion; 5-FU 400 mg/m2 intravenous infusion; 5-FU 2400 mg/m2 intravenous infusion

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Colorectal adenocarcinoma verified by biopsy.

2. Availability of biopsy material, from the primary tumor or metastasis, allowing for analysis of tumor gene expression.

3. Non-resectable metastatic CRC planned for first line therapy with 5-FU, Leucovorin, oxaliplatin, and bevacizumab.

4. Evaluable disease with at least one measurable lesion of metastatic disease (≥10 mm in longest diameter on axial image on CT-scan or alternatively MRI with <5 mm reconstruction interval) or lymph node (≥ 15 mm in shortest axis when assessed by CT) obtained within 28 days of randomization.

5. Life expectancy of more than 4 months.

6. ECOG performance status 0 or 1.

7. Hemoglobin (Hb) > 80 g/L, Absolute neutrophil count (ANC) > 1.5x10E9/L. Thrombocytes > 100x10E9/L.

8. Creatinine clearance > 50 mL/min, Total bilirubin < 1.5 x ULN, AST and ALT < 3 x ULN (and < 5 x ULN in case of liver metastases).

9. Male or female ≥18 years of age.

10. Female patients of childbearing potential must have a negative urine pregnancy test and use adequate contraceptive measures . Male patients must use adequate contraceptive measures .

11. Voluntarily signed informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria

1. Malignant tumors other than colorectal adenocarcinomas (current or within the previous five years), with the exception for curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix.

2. Less than 6 months between randomization and completion of the last anti-cancer treatment (chemotherapy/radiotherapy/immunotherapy, etc.). (NB: Rectal cancer treatment shorter than 8 weeks of chemo/radiation therapy is allowed.)

3. Confirmation of progressive disease within 6 months after completion of prior adjuvant anti-cancer treatment.

4. Indication for any metastatic Colo-rectal Cancer (mCRC) surgery or anti-cancer treatment other than study treatment.

5. Prior treatment with arfolitixorin.

6. Indication for treatment with a 5-FU analogue, or 5-FU for a condition other than mCRC.

7. Known Dihydropyrimidine Dehydrogenase Deficiency (DPD) deficiency.

8. Known or suspected central nervous system (CNS) metastases.

9. Unresolved bowel obstruction, uncontrolled Crohn's disease, or ulcerative colitis.

10. History of cardiac disease with a New York Heart Association Class II or greater, congestive heart failure, myocardial infarction, or unstable angina at any time during the 6 months prior to randomization, or serious arrhythmias requiring medication for treatment.

11. Current CTCAE ≥ grade 3 diarrhea.

12. Current chronic infection or uncontrolled serious illness causing immunodeficiency.

13. Known or suspected hypersensitivity or intolerance to arfolitixorin, LV, 5-FU, oxaliplatin, or bevacizumab.

14. Breastfeeding patients.

15. Patient who received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug, prior to randomization.

16. Patient with serious medical or psychiatric illness likely to interfere with participation in this clinical study.

17. Ongoing drug or alcohol abuse, as deemed by the Investigator.

18. Any condition that, in the opinion of the Investigator, could compromise the patient's safety or adherence to the study protocol.

19. Involvement, or related to people involved in the planning or conduct of the study (applies to both Isofol Medical AB (publ) staff and staff at the study site)

20. Surgery (excluding previous diagnostic biopsy) in the 28-day period before randomization

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Isofol Medical AB

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Josep Tabernero, Prof.

Role: PRINCIPAL_INVESTIGATOR

Vall d'Hebron Institute of Oncology

Locations

840-24 - Banner Gateway Medical Center

Gilbert, Arizona, United States

840-15 - University of Southern California

Los Angeles, California, United States

840-01 - HOAG Memorial Hospital

Newport Beach, California, United States

840-13 - UCH-MHS d/b/a Memorial Health System

Colorado Springs, Colorado, United States

840-34 - Banner MD Anderson Cancer Center

Greeley, Colorado, United States

840-32 - University of Miami

Miami, Florida, United States

840-08 - Pinellas Hematology Oncology

St. Petersburg, Florida, United States

840-30 - Joliet Oncology-Hematology Associates

Joliet, Illinois, United States

840-06 - Cancer Center of Kansas

Wichita, Kansas, United States

840-29 - Ashland-Bellefonte Cancer Center

Ashland, Kentucky, United States

840-19 - University of Louisville Research Foundation Inc. (ULRF)

Louisville, Kentucky, United States

840-14 - University of Michigan Cancer Center

Ann Arbor, Michigan, United States

840-04 - St. Vincent Frontier Cancer Center

Billings, Montana, United States

840-12 - Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

840-22 - University of Oklahoma Stephenson Cancer Center

Oklahoma City, Oklahoma, United States

840-10 - Oregon Health and Science University-Knight Cancer Institute

Portland, Oregon, United States

840-27 - Charleston Hematology Oncology Associates

Charleston, South Carolina, United States

840-02 - The University of Texas Health Science Center

San Antonio, Texas, United States

036-10 - Border Medical Oncology Research Unit

Albury, New South Wales, Australia

036-02 - Chris O'Brien Lifehouse

Sydney, New South Wales, Australia

036-03 - Westmead Hospital

Sydney, New South Wales, Australia

036-09 - Southern Medical Day Care Center

Wollongong, New South Wales, Australia

036-04 - Peninsula Health - Frankston Hospital

Frankston, Victoria, Australia

036-01 - Western Health - Sunshine Hospital

Melbourne, Victoria, Australia

036-07 - Northern Health - Epping Hospital

Melbourne, Victoria, Australia

036-05 - Monash Health

Melbourne, Victoria, Australia

040-02 - Klinikum Klagenfurt am Wörthersee

Klagenfurt, , Austria

040-06 - Ordensklinikum Linz GmbH - Barmherzige Schwestern

Linz, , Austria

040-03 - Uniklinikum Salzburg

Salzburg, , Austria

040-01 - Allgemeines Krankenhaus der Stadt Wien

Vienna, , Austria

040-05 - Wilhelminenspital

Vienna, , Austria

040-04 - Landesklinikum Wiener Neustadt

Wiener Neustadt, , Austria

124-03 - William Osler Health System - Brampton Civi Hospital

Brampton, Ontario, Canada

124-10 - Thunder Bay Regional Health Research Institute

Thunder Bay, Ontario, Canada

124-07 - Sunnybrook Research Institute

Toronto, Ontario, Canada

124-04 - CISSS de l'Outaouais - Hôpital de Gatineau

Gatineau, Quebec, Canada

124-11 - CISSS de Chaudière-Appalaches

Lévis, Quebec, Canada

124-01 - Montreal University Health Center

Montreal, Quebec, Canada

124-02 - Hôpital de la Cité-de-la-Santé

Laval, , Canada

124-08 - Hôpital Maisonneuve Rosemont

Montreal, , Canada

124-06 - Jewish General Hospital

Montreal, , Canada

124-05 - Ottawa Hospital Research Institute

Ottawa, , Canada

250-07 - Hôpital Henri Mondor

Créteil, , France

250-06 - Centre Georges Francois Leclerc

Dijon, , France

250-01 - Institute Hospitalier Franco-Britannique

Levallois-Perret, , France

250-09 - Hopital Privé Jean Mermoz

Lyon, , France

250-08 - Hôpital Européen

Marseille, , France

250-03 - Hôpital Paris Saint Joseph

Paris, , France

250-02 - Hôpital Saint-Antoine

Paris, , France

250-04 - Polyclinique Francheville

Périgueux, , France

250-05 - Clinique Sainte Anne

Strasbourg, , France

276-12 - Charité - Universitätsmedizin Berlin

Berlin, , Germany

276-02 - Universitätsklinikum Carl Gustav Carus

Dresden, , Germany

276-03 - Krankenhaus Nordwest GmbH

Frankfurt am Main, , Germany

276-10 - Universitärers Cancer Center Hamburg (UCCH)

Hamburg, , Germany

276-11 - Klinikum Kassel GmbH

Kassel, , Germany

276-04 - MVZ Mitte - Onkologische Schwerpunktpraxis

Leipzig, , Germany

276-13 - Universitäres Krebszentrum Leipzig (UCCL)

Leipzig, , Germany

276-07 - Philipps-Universität Marburg

Marburg, , Germany

276-08 - Carl von Basedow Klinikum Saalekrei GmbH

Merseburg, , Germany

276-01 - Klinikum der Universität München - Campus Grosshadern

München, , Germany

276-09 - Klinikum Nürnberg Nord

Nuremberg, , Germany

276-05 - Kliniken Nordoberpfalz AG

Weiden, , Germany

300-04 - 251 Airforce Hospital

Athens, , Greece

300-01 - Aretaieo Hospital

Athens, , Greece

300-02 - University General Hospital Attikon

Athens, , Greece

300-03 - Metropolitan General Hospital

Athens, , Greece

300-05 - Metropolitan General SA

Athens, , Greece

300-06 - University General Hospital of Larissa

Larissa, , Greece

392-10 - Aichi Cancer Center

Aichi, , Japan

392-01 - National Cancer Center Hospital East

Chiba, , Japan

392-09 - National Hospital Organization Shikoku Cancer Center

Ehime, , Japan

392-07 - Gifu University Hospital

Gifu, , Japan

392-12 - Saitama Medical University International Medical Center

Hidaka, , Japan

392-05 - University of Tsukuba Hospital

Ibaraki, , Japan

392-15 - Kagawa University Hospital

Kagawa, , Japan

392-08 - St.Marianna University School of Medicine Hospital

Kanagawa, , Japan

392-11 - National Hospital Organization Osaka National Hospital

Osaka, , Japan

392-13 - Osaka General Medical Center

Osaka, , Japan

392-14 - Kansai Medical University Hospital

Osaka, , Japan

392-04 - Saitama Cancer Center

Saitama, , Japan

392-03 - Hokkaido University Hospital

Sapporo Hokkaido, , Japan

392-02 - Shizuoka Cancer Center

Shizuoka, , Japan

392-06 - National Cancer Center Hospital

Tokyo, , Japan

724-03 - Instituto Oncologico Baselga - Hospital Quiron

Barcelona, , Spain

724-07 - Hospital del la Santa Creu i Sant Pau

Barcelona, , Spain

724-01 - Vall d'Hebron Institute of Oncology

Barcelona, , Spain

724-06 - Hospital Universitario Reina Sofia

Córdoba, , Spain

724-04 - Hospital Unviersitario 12 de Octubre

Madrid, , Spain

724-09 - Hospital Universitario HM Sanchinarro

Madrid, , Spain

724-02 - Hospital Regional Universitario Carlos Haya

Málaga, , Spain

724-05 - Hospital Universitario Virgen del Rocío

Seville, , Spain

752-02 - Södersjukhuset

Stockholm, , Sweden

752-01 - Akademiska Sjukhuset

Uppsala, , Sweden

Countries

United States; Australia; Austria; Canada; France; Germany; Greece; Japan; Spain; Sweden

References

Tabernero J, Yoshino T, Stintzing S, de Gramont A, Gibbs P, Jonker DJ, Nygren P, Papadimitriou C, Prager GW, Tell R, Lenz HJ. A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial. Cancer Res Commun. 2024 Jan 4;4(1):28-37. doi: 10.1158/2767-9764.CRC-23-0361.

Reference Type: DERIVED

PMID: 38059497 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

ISO-CC-007

Identifier Type: -

Identifier Source: org_study_id