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

A Randomized, Multicenter, Parallel-group, Phase III Study to Compare the Efficacy of Arfolitixorin Versus Leucovorin in Combination With 5 Fluorouracil, Oxaliplatin, and Bevacizumab in Patients With Advanced Colorectal Cancer

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.

Study Overview

• Status: Completed
• Conditions: Colo-rectal Cancer
• Intervention / Treatment: Drug: Arfolitixorin; Drug: Leucovorin

• Study Type: Interventional
• Enrollment (Actual): 490
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • 036-10 - Border Medical Oncology Research Unit
    • Sydney, New South Wales, Australia, 2050
      • 036-02 - Chris O'Brien Lifehouse
    • Sydney, New South Wales, Australia, 2145
      • 036-03 - Westmead Hospital
    • Wollongong, New South Wales, Australia, 2500
      • 036-09 - Southern Medical Day Care Center
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • 036-04 - Peninsula Health - Frankston Hospital
    • Melbourne, Victoria, Australia, 3021
      • 036-01 - Western Health - Sunshine Hospital
    • Melbourne, Victoria, Australia, 3076
      • 036-07 - Northern Health - Epping Hospital
    • Melbourne, Victoria, Australia, 3168
      • 036-05 - Monash Health
• Austria
  • Klagenfurt, Austria, 9020
    • 040-02 - Klinikum Klagenfurt am Wörthersee
  • Linz, Austria, 4010
    • 040-06 - Ordensklinikum Linz GmbH - Barmherzige Schwestern
  • Salzburg, Austria, 5020
    • 040-03 - Uniklinikum Salzburg
  • Wien, Austria, 1090
    • 040-01 - Allgemeines Krankenhaus der Stadt Wien
  • Wien, Austria, 1160
    • 040-05 - Wilhelminenspital
  • Wiener Neustadt, Austria, 2700
    • 040-04 - Landesklinikum Wiener Neustadt
• Canada
  • Laval, Canada, H7M 3L9
    • 124-02 - Hôpital de la Cité-de-la-Santé
  • Montréal, Canada, H1T 2M4
    • 124-08 - Hôpital Maisonneuve Rosemont
  • Montréal, Canada, H3T 1E2
    • 124-06 - Jewish General Hospital
  • Ottawa, Canada, KIH8L6
    • 124-05 - Ottawa Hospital Research Institute
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • 124-03 - William Osler Health System - Brampton Civi Hospital
    • Thunder Bay, Ontario, Canada, P7B 6V4
      • 124-10 - Thunder Bay Regional Health Research Institute
    • Toronto, Ontario, Canada, M4N 3M5
      • 124-07 - Sunnybrook Research Institute
  • Quebec
    • Gatineau, Quebec, Canada, J8V 2L4
      • 124-04 - CISSS de l'Outaouais - Hôpital de Gatineau
    • Lévis, Quebec, Canada, G6V 3Z1
      • 124-11 - CISSS de Chaudière-Appalaches
    • Montreal, Quebec, Canada, H4A 3J1
      • 124-01 - Montreal University Health Center
• France
  • Créteil, France, 94010
    • 250-07 - Hôpital Henri Mondor
  • Dijon, France, 21000
    • 250-06 - Centre Georges Francois Leclerc
  • Levallois-Perret, France, 92300
    • 250-01 - Institute Hospitalier Franco-Britannique
  • Lyon, France, 69373
    • 250-09 - Hopital Privé Jean Mermoz
  • Marseille, France, 13003
    • 250-08 - Hôpital Européen
  • Paris, France, 75014
    • 250-03 - Hôpital Paris Saint Joseph
  • Paris, France, 75571
    • 250-02 - Hôpital Saint-Antoine
  • Périgueux, France, 24000
    • 250-04 - Polyclinique Francheville
  • Strasbourg, France, 67000
    • 250-05 - Clinique Sainte Anne
• Germany
  • Berlin, Germany, 10117
    • 276-12 - Charité - Universitätsmedizin Berlin
  • Dresden, Germany, 01307
    • 276-02 - Universitätsklinikum Carl Gustav Carus
  • Frankfurt am Main, Germany, 60488
    • 276-03 - Krankenhaus Nordwest GmbH
  • Hamburg, Germany, 20246
    • 276-10 - Universitärers Cancer Center Hamburg (UCCH)
  • Kassel, Germany, 34125
    • 276-11 - Klinikum Kassel GmbH
  • Leipzig, Germany, 04103
    • 276-04 - MVZ Mitte - Onkologische Schwerpunktpraxis
  • Leipzig, Germany, 04103
    • 276-13 - Universitäres Krebszentrum Leipzig (UCCL)
  • Marburg, Germany, 35032
    • 276-07 - Philipps-Universität Marburg
  • Merseburg, Germany, 06217
    • 276-08 - Carl von Basedow Klinikum Saalekrei GmbH
  • München, Germany, 81377
    • 276-01 - Klinikum der Universität München - Campus Grosshadern
  • Nürnberg, Germany, 90419
    • 276-09 - Klinikum Nürnberg Nord
  • Weiden, Germany, 92637
    • 276-05 - Kliniken Nordoberpfalz AG
• Greece
  • Athen, Greece, 15562
    • 300-05 - Metropolitan General SA
  • Athens, Greece, 11525
    • 300-04 - 251 Airforce Hospital
  • Athens, Greece, 11528
    • 300-01 - Aretaieo Hospital
  • Athens, Greece, 15562
    • 300-02 - University General Hospital Attikon
  • Athens, Greece, 15562
    • 300-03 - Metropolitan General Hospital
  • Larissa, Greece, 41110
    • 300-06 - University General Hospital of Larissa
• Japan
  • Aichi, Japan, 464-8681
    • 392-10 - Aichi Cancer Center
  • Chiba, Japan, 277-8577
    • 392-01 - National Cancer Center Hospital East
  • Ehime, Japan, 791-0280
    • 392-09 - National Hospital Organization Shikoku Cancer Center
  • Gifu City, Japan, 501-1194
    • 392-07 - Gifu University Hospital
  • Hidaka City, Japan, 350-1298
    • 392-12 - Saitama Medical University International Medical Center
  • Ibaraki, Japan, 305-8576
    • 392-05 - University of Tsukuba Hospital
  • Kagawa, Japan, 761-0793
    • 392-15 - Kagawa University Hospital
  • Kanagawa, Japan, 216-8511
    • 392-08 - St.Marianna University School of Medicine Hospital
  • Osaka, Japan, 540-0006
    • 392-11 - National Hospital Organization Osaka National Hospital
  • Osaka, Japan, 558-8558
    • 392-13 - Osaka General Medical Center
  • Osaka, Japan, 573-1191
    • 392-14 - Kansai Medical University Hospital
  • Saitama, Japan, 362-0806
    • 392-04 - Saitama Cancer Center
  • Sapporo Hokkaido, Japan, 060-8648
    • 392-03 - Hokkaido University Hospital
  • Shizuoka, Japan, 411-8777
    • 392-02 - Shizuoka Cancer Center
  • Tokyo, Japan, 104-0045
    • 392-06 - National Cancer Center Hospital
• Spain
  • Barcelona, Spain, 08023
    • 724-03 - Instituto Oncologico Baselga - Hospital Quiron
  • Barcelona, Spain, 08026
    • 724-07 - Hospital del la Santa Creu i Sant Pau
  • Barcelona, Spain, 08035
    • 724-01 - Vall d'Hebron Institute of Oncology
  • Córdoba, Spain, 14004
    • 724-06 - Hospital Universitario Reina Sofia
  • Madrid, Spain, 28041
    • 724-04 - Hospital Unviersitario 12 de Octubre
  • Madrid, Spain, 28050
    • 724-09 - Hospital Universitario HM Sanchinarro
  • Málaga, Spain, 29010
    • 724-02 - Hospital Regional Universitario Carlos Haya
  • Sevilla, Spain, 41013
    • 724-05 - Hospital Universitario Virgen del Rocío
• Sweden
  • Stockholm, Sweden, 118 83
    • 752-02 - Södersjukhuset
  • Uppsala, Sweden, 751 85
    • 752-01 - Akademiska Sjukhuset
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • 840-24 - Banner Gateway Medical Center
  • California
    • Los Angeles, California, United States, 91001
      • 840-15 - University of Southern California
    • Newport Beach, California, United States, 92663
      • 840-01 - HOAG Memorial Hospital
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • 840-13 - UCH-MHS d/b/a Memorial Health System
    • Greeley, Colorado, United States, 80631
      • 840-34 - Banner MD Anderson Cancer Center
  • Florida
    • Miami, Florida, United States, 33136
      • 840-32 - University of Miami
    • Saint Petersburg, Florida, United States, 33709
      • 840-08 - Pinellas Hematology Oncology
  • Illinois
    • Joliet, Illinois, United States, 60435
      • 840-30 - Joliet Oncology-Hematology Associates
  • Kansas
    • Wichita, Kansas, United States, 67214
      • 840-06 - Cancer Center of Kansas
  • Kentucky
    • Ashland, Kentucky, United States, 41101
      • 840-29 - Ashland-Bellefonte Cancer Center
    • Louisville, Kentucky, United States, 40202-1798
      • 840-19 - University of Louisville Research Foundation Inc. (ULRF)
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • 840-14 - University of Michigan Cancer Center
  • Montana
    • Billings, Montana, United States, 59102
      • 840-04 - St. Vincent Frontier Cancer Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • 840-12 - Rutgers Cancer Institute of New Jersey
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • 840-22 - University of Oklahoma Stephenson Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • 840-10 - Oregon Health and Science University-Knight Cancer Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • 840-27 - Charleston Hematology Oncology Associates
  • Texas
    • San Antonio, Texas, United States, 78229
      • 840-02 - The University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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: Group A; ARFOX (Arfolitixorin and 5-FU and Oxaliplatin) and Bevacizumab	Drug: 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
Active Comparator: Group B; mFOLFOX-6 (Leucovorin and 5-FU and Oxaliplatin) and Bevacizumab	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Best ORR, defined as the best response recorded from the start of the study treatment until the end of treatment.	Until disease progression, an average of ten months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	PFS, defined as the time from randomization to first occurrence of tumor progression based on CT-scans/MRIs.	Until disease progression, an average of ten months
Duration of Response	The duration of response is measured from the time measurement criteria are first met for CR/PR until the first date that recurrent or progressive disease is objectively documented.	Until disease progression, an average of ten months

Collaborators and Investigators

• Sponsor: Isofol Medical AB
• Investigators: Principal Investigator: Josep Tabernero, Prof., Vall d'Hebron Institute of Oncology

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2018
• Primary Completion (Actual): November 18, 2022
• Study Completion (Actual): November 18, 2022

Study Registration Dates

• First Submitted: November 19, 2018
• First Submitted That Met QC Criteria: November 20, 2018
• First Posted (Actual): November 23, 2018

Study Record Updates

• Last Update Posted (Actual): October 26, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Leucovorin
• Other Study ID Numbers: ISO-CC-007

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No