TWICE-IRI: Optimization of Second-line Therapy With Aflibercept, Irinotecan (Day 1 or Day 1,3), 5-Fluorouracile and Folinic Acid in Patients With Metastatic Colorectal Cancer. A Randomized Phase III Study.

NCT04392479 | Unknown Phase 3 DMC

• 1 other identifier: FBH-002
• Study Type: interventional
• Target: 202
• Locations: 1 country
• Sites: 1

Brief Summary

Optimization of second-line therapy with aflibercept, irinotecan (day1 or day 1,3), 5fluorouracile and folinic acid in patients with metastatic colorectal cancer. A randomized Phase III study.

Conditions

Cancer Colorectal; Metastasis

Keywords

Aflibercept

Outcome Measures

Primary Outcomes (1)

• Overall response rate (ORR).

  Tumor measurements will be obtained using CT-scans (or MRIs) of the thorax, abdomen, and pelvis at baseline then every 8 weeks (+/- one week) according to RECIST v1.1. At the investigator's discretion, tumor assessments may be repeated at any time if progressive disease is suspected. It is preferred that the scans for a patient are taken with the same technique (CT or MRI) throughout the study.

  2 months

Secondary Outcomes (9)

• Disease control rate (DCR)

  2 months

• Early response rate

  2 months

• Progression-free survival (PFS)

  2 months

• Overall survival (OS)

  time interval from randomization to the date of death from any cause. Assessed up to 13 months after the beginning of the study

• Salvage surgery rate

  2 months

Study Arms (2)

Aflibercept-FOLFIRI (arm 1)

ACTIVE COMPARATOR

* Aflibercept (D1) H0: 4mg/kg IV infusion over 60min (+ 2-minute window), * Folinic acid (D1) H+1: 400mg/m² IV infusion over 120min (+ 2-minute window), * Irinotecan (D1) H+1: 180mg/m² IV infusion over 60min (+ 2-minute window), * 5-fluorouracile (D1) H+3: 400mg/m² IV infusion over 15min (+ 2-minute window), * 5-fluorouracile (D1 to D3): H+3.5: 2400mg/m² IV infusion over 46 hours (+ 1hour window) * H+49.5: End of treatment administration

Drug: Aflibercept-FOLFIRI

Aflibercept-mFOLFIRI3 (arm 2)

EXPERIMENTAL

* Aflibercept (D1) H0: 4mg/kg IV infusion over 60min (+ 2-minute window), * Folinic acid (D1) H+1: 400mg/m² IV infusion over 120min (+ 2-minute window), * Irinotecan (D1 and D3) H+1 and H+49: 75mg/m² IV infusion over 60min (+ 2-minute window) on cycles 1 and 2, then 90mg/m² at cycle 3 and furthers in absence of AEs grade ≥2, * 5-fluorouracile (D1 to D3) H+3: 2400mg/m² IV infusion over 46 hours (+ 1hour window) * H+50: End of treatment administration

Drug: Aflibercept-mFOLFIRI3

Interventions

Aflibercept-FOLFIRI DRUG

Aflibercept-FOLFIRI

Also known as: ZALTRAP-FOLFIRI

Aflibercept-FOLFIRI (arm 1)

Aflibercept-mFOLFIRI3 DRUG

Aflibercept-mFOLFIRI3

Also known as: ZALTRAP- mFOLFIRI3

Aflibercept-mFOLFIRI3 (arm 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated informed consent and stated willingness to comply with all study procedures and availability for the duration of the study, Signed, written Informed Consent Form (ICF),
• Willing and able to comply with the protocol,
• Age 18-75 years,
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1,
• Life expectancy ≥ 3 months,
• Histologically proven carcinoma of colon and/or rectum,
• Confirmed unresectable metastatic disease,
• At least one measurable and/or evaluable tumor metastasis on CT-scan or MRI per RECIST criteria version 1.1,
• Prior oxaliplatin-based first-line therapy for metastatic disease (the use of prior bevacizumab or anti-EGFR mabs is allowed but not mandatory) - Less than 6 months from completion of any prior oxaliplatin-based adjuvant therapy can be considered as first-line therapy. Prior use of irinotecan in combination with oxaliplatin and 5FU as first-line therapy is allowed if the interval between the last administration of irinotecan and disease progression is at least 6 months (ie, irinotecan-free interval ≥6 months).
• Clinical laboratory parameters adequate as follows:
• Serum total bilirubin level ≤ 1.5 x upper normal limit (UNL),
• Neutrophil count ≥ 1.5x109/L,
• Platelet count ≥ 100x109/L,
• Hemoglobin ≥ 9 g/dL,
• Serum creatinine level ≤ 150µM,

You may not qualify if:

• History of arterial thrombotic event in the last 6 months (eg., myocardial infarction, cerebrovascular accident or transient ischemic attack),
• Uncontrolled hypertension (defined as systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg despite optimal medical therapy), or history of hypertensive crisis, or hypertensive encephalopathy,
• Prior use of aflibercept,
• Adverse events from prior anticancer therapy grade ≥2 (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] version 5.0), except for neuropathy and alopecia,
• Bowel obstruction, inflammatory bowel disease
• Known DPD deficiency. If not known for the patient, testing for DPD should be done during the screening period (patients with uracilemia ≥16ng/mL are not eligible),
• Known UGT1A1 deficiency (eg, Gilbert syndrome, Crigler-Najjar syndrome). If not known for the patient, genetic testing for UGT1A1 should be done during the screening period for patients with hyperbilirubinemia (ie, total bilirubin level \>1xULN),
• Active infection requiring intravenous antibiotics at the start of study treatment,
• Known active infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV),
• Known allergy or hypersensitivity to the active substance or ingredients of any study drug,
• Women currently pregnant or breastfeeding,
• Inability to comply with study and follow-up procedures as judged by the Investigator,
• Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy)
• Concomitant use of Saint John Wort herb (millepertuis), Yellow Fever vaccine, Live Attenuated Vaccines (LAV) and phenytoine
• Treatment with any other investigational medicinal product within 28 days or 5 investigational agent half-lives (whichever is longer) prior to the start of study treatment,

Sponsors & Collaborators

• Fondation ARCAD: collaborator
• Hôpital Franco-Britannique-Fondation Cognacq-Jay: lead

Study Sites (1)

Franco-British Hospital - GCS IHFB Cognacq-Jay

Levallois-Perret, 92300, France

Location

Related Publications (19)

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12.

  PMID: 30207593 BACKGROUND

• Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. doi: 10.1200/JCO.2004.05.113. Epub 2003 Dec 2.

  PMID: 14657227 BACKGROUND

• Jolivet J. Role of leucovorin dosing and administration schedule. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1311-5. doi: 10.1016/0959-8049(95)00140-e.

  PMID: 7577042 BACKGROUND

• Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. doi: 10.1200/JCO.2012.42.8201. Epub 2012 Sep 4.

  PMID: 22949147 BACKGROUND

• Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. doi: 10.1200/JCO.2009.27.6055. Epub 2010 Oct 4.

  PMID: 20921462 BACKGROUND

• Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausova J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12.

  PMID: 25877855 BACKGROUND

• Guichard S, Cussac D, Hennebelle I, Bugat R, Canal P. Sequence-dependent activity of the irinotecan-5FU combination in human colon-cancer model HT-29 in vitro and in vivo. Int J Cancer. 1997 Nov 27;73(5):729-34. doi: 10.1002/(sici)1097-0215(19971127)73:53.0.co;2-#.

  PMID: 9398054 BACKGROUND

• Mullany S, Svingen PA, Kaufmann SH, Erlichman C. Effect of adding the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN-38) to 5-fluorouracil and folinic acid in HCT-8 cells: elevated dTTP pools and enhanced cytotoxicity. Cancer Chemother Pharmacol. 1998;42(5):391-9. doi: 10.1007/s002800050835.

  PMID: 9771954 BACKGROUND

• Mans DR, Grivicich I, Peters GJ, Schwartsmann G. Sequence-dependent growth inhibition and DNA damage formation by the irinotecan-5-fluorouracil combination in human colon carcinoma cell lines. Eur J Cancer. 1999 Dec;35(13):1851-61. doi: 10.1016/s0959-8049(99)00222-1.

  PMID: 10674003 BACKGROUND

• Falcone A, Di Paolo A, Masi G, Allegrini G, Danesi R, Lencioni M, Pfanner E, Comis S, Del Tacca M, Conte P. Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients. J Clin Oncol. 2001 Aug 1;19(15):3456-62. doi: 10.1200/JCO.2001.19.15.3456.

  PMID: 11481350 BACKGROUND

• Mabro M, Louvet C, Andre T, Carola E, Gilles-Amar V, Artru P, Krulik M, de Gramont A; GERCOR. Bimonthly leucovorin, infusion 5-fluorouracil, hydroxyurea, and irinotecan (FOLFIRI-2) for pretreated metastatic colorectal cancer. Am J Clin Oncol. 2003 Jun;26(3):254-8. doi: 10.1097/01.COC.0000020581.59835.7A.

  PMID: 12796595 BACKGROUND

• Mabro M, Artru P, Andre T, Flesch M, Maindrault-Goebel F, Landi B, Lledo G, Plantade A, Louvet C, de Gramont A. A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients. Br J Cancer. 2006 May 8;94(9):1287-92. doi: 10.1038/sj.bjc.6603095.

  PMID: 16622455 BACKGROUND

• Bidard FC, Tournigand C, Andre T, Mabro M, Figer A, Cervantes A, Lledo G, Bengrine-Lefevre L, Maindrault-Goebel F, Louvet C, de Gramont A. Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study. Ann Oncol. 2009 Jun;20(6):1042-7. doi: 10.1093/annonc/mdn730. Epub 2009 Jan 19.

  PMID: 19153116 BACKGROUND

• Chibaudel B, Maindrault-Goebel F, Bachet JB, Louvet C, Khalil A, Dupuis O, Hammel P, Garcia ML, Bennamoun M, Brusquant D, Tournigand C, Andre T, Arbaud C, Larsen AK, Wang YW, Yeh CG, Bonnetain F, de Gramont A. PEPCOL: a GERCOR randomized phase II study of nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with leucovorin/5-fluorouracil as second-line therapy in metastatic colorectal cancer. Cancer Med. 2016 Apr;5(4):676-83. doi: 10.1002/cam4.635. Epub 2016 Jan 24.

  PMID: 26806397 BACKGROUND

• Carola C, Ghiringhelli F, Kim S, Andre T, Barlet J, Bengrine-Lefevre L, Marijon H, Garcia-Larnicol ML, Borg C, Dainese L, Steuer N, Richa H, Benetkiewicz M, Larsen AK, de Gramont A, Chibaudel B. FOLFIRI3-aflibercept in previously treated patients with metastatic colorectal cancer. World J Clin Oncol. 2018 Sep 14;9(5):110-118. doi: 10.5306/wjco.v9.i5.110.

  PMID: 30254966 BACKGROUND

• Ghiringhelli F, Vincent J, Beltjens F, Bengrine L, Ladoire S. Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients. Invest New Drugs. 2015 Dec;33(6):1263-6. doi: 10.1007/s10637-015-0295-6. Epub 2015 Oct 22.

  PMID: 26490656 BACKGROUND

• Rubbia-Brandt L, Giostra E, Brezault C, Roth AD, Andres A, Audard V, Sartoretti P, Dousset B, Majno PE, Soubrane O, Chaussade S, Mentha G, Terris B. Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann Oncol. 2007 Feb;18(2):299-304. doi: 10.1093/annonc/mdl386. Epub 2006 Oct 23.

  PMID: 17060484 BACKGROUND

• Blazer DG 3rd, Kishi Y, Maru DM, Kopetz S, Chun YS, Overman MJ, Fogelman D, Eng C, Chang DZ, Wang H, Zorzi D, Ribero D, Ellis LM, Glover KY, Wolff RA, Curley SA, Abdalla EK, Vauthey JN. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol. 2008 Nov 20;26(33):5344-51. doi: 10.1200/JCO.2008.17.5299. Epub 2008 Oct 20.

  PMID: 18936472 BACKGROUND

• Bonnetain F, Dahan L, Maillard E, Ychou M, Mitry E, Hammel P, Legoux JL, Rougier P, Bedenne L, Seitz JF. Time until definitive quality of life score deterioration as a means of longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma. Eur J Cancer. 2010 Oct;46(15):2753-62. doi: 10.1016/j.ejca.2010.07.023. Epub 2010 Aug 17.

  PMID: 20724140 BACKGROUND

MeSH Terms

Conditions

Colonic Neoplasms; Neoplasm Metastasis

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Benoist CHIBAUDEL, MD

  Franco-British Hospital GCS IHFB Cognacq-Jay

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2020
• First Posted: May 18, 2020
• Study Start: September 2, 2020
• Primary Completion: June 15, 2023
• Study Completion: June 1, 2024
• Last Updated: October 23, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)