Cancer ColorectalPhase 3TWICE-IRINCT04392479

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.

A Phase 3 study testing Aflibercept-FOLFIRI and Aflibercept-mFOLFIRI3 in people with Cancer Colorectal and Metastasis, run by Hôpital Franco-Britannique-Fondation Cognacq-Jay at 1 site in France.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Cancer Colorectal, Metastasis
What is being tested?: Aflibercept-FOLFIRI and Aflibercept-mFOLFIRI3
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 202 participants
Where: 1 siteFrance
Study dates: 2 Sep 2020to Jun 2024
Phase: Phase 3
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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,

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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).
Negative urine and/or serum pregnancy test within 7 days before inclusion if female subject is of childbearing potential,
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,
Serum albumin ≥ 25 g/L,
Calcium ≥ 1 x ULN
Alkaline phosphatase (ALP) < 3 x ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN (in the case of liver metastases, <5 x ULN),
Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour,
For women of childbearing potential and for men, agreement to use an effective contraceptive method from the time of screening throughout the study until 6 months after administration of the last dose of any study medication. Highly effective contraceptive method consist of prior sterilization, inter-uterine device, intrauterine hormone-releasing system, oral or injectable contraceptives barrier methods, and/or true sexual abstinence),
Affiliation to French health care system.

Who cannot join

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),

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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,
Any other disease, active, uncontrolled bacterial, viral or fungal infection requiring systemic therapy, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of a disease or condition that contraindicates the use of study drugs that may affect the interpretation of the results, or that may render the subject at high risk for treatment complications.
Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for three years prior to study entry,
Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to start of study treatment, or anticipation of need for major surgical procedure during the course of the study.
Minor surgical procedure including placement of a vascular access device, within 2 days of start of study treatment,
History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to start study treatment.
Clinically significant active cardiac disease (including NYHA class III or IV congestive heart failure)
Venous thromboembolic event (including pulmonary embolism) grade 3 or 4 within 6 months prior to start study treatment.

Trial locations and contacts

1 site in 1 country.

France1 site

Franco-British Hospital - GCS IHFB Cognacq-Jay
Levallois-Perret, 92300

Other trials in France

About this study

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.

Read the detailed description

Background - Rationale Aflibercept The addition of aflibercept to the standard FOLFIRI regimen as second-line therapy was evaluated in a large phase III study (EFC10262-VELOUR). This combination significantly improved both PFS (4.7 to 6.9 months, HR=0.76; P=<0.001) and OS (12.1 to 13.5 months, HR=0.82; P=0.003). In the evaluable population (86.5%), the tumor response rate was also improved when adding aflibercept (ORR=19.8% [16.4-23.2]) to the FOLFIRI regimen (ORR=11.1% [8.5-13.8]).

Irinotecan The combination of aflibercept with FOLFIRI3, an optimized irinotecan-based regimen, was evaluated in 65 patients in a French multicentric retrospective cohort. (Carola C et al, WJCO 2018) In the cohort of irinotecan-naïve patients (n=30), the objective response rate was 43.3%, and the disease control rate 76.7%. Median PFS and OS were 11.3 months (95% CI 6.1-29.0) and 17.0 months (95% CI 13.0-17.3). The most common (>5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), hypertension (6.7%).

In the cohort of patients previously treated with irinotecan (n=35), the objective response rate was 34.3%, and the disease control rate 60.0%. Median PFS and OS were 5.7 months (95% CI 3.9-10.4) and 14.3 months (95% CI 12.8-19.5).

Table. FOLFIRI-aflibercept vs. FOLFIRI3-aflibercept: a cross-trial comparison FOLFIRI-aflibercept (VELOUR) FOLFIRI3-aflibercept (Irinotecan-naïve) N = 612 N = 30 Efficacy RR, % 19.3 vs 43.3 PFS, months 6.9 vs 11.3 OS, months 13.5 vs 17.0 Grade 3-4 AEs, % Any 83.4 vs 56.7 Neutropenia 36.7 vs 14.3 Diarrhea 19.3 vs 37.9 Mucositis 13.8 vs 10.4 Hypertension 19.3 vs 6.9 Discontinuation, % Progression 49.8 vs 36.7 Adverse event 26.6 vs 46.7

Study Objectives

Primary:

•To compare once (day 1) or twice (day 1, day 3) administration of irinotecan in combination with 5-fluorouracile and aflibercept as second-line therapy in patients with metastatic colorectal cancer in terms of overall response rate (ORR)

Secondary:

To evaluate disease control rate (DRC) and Early Response Rate (ERR)
To evaluate progression-free survival (PFS) and overall survival (OS),
to evaluate the conversion rate to locoregional therapy, surgery of metastasis, the quality of resection (R0, R1, R2) and the pathological response in patients with resected metastatic disease,
To assess the impact on health-related quality of life (HRQOL) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30),
To assess Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) on using the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 5.0).

Exploratory:

To assess the impact on selected circulating biomarkers (angiogenic and exosomal)
To assess the impact on selected tumor biomarkers

Conditions: Cancer Colorectal, Metastasis
Being tested: Aflibercept-FOLFIRI, Aflibercept-mFOLFIRI3
Keywords: Aflibercept
Medical subject headings: Colonic Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Aflibercept-FOLFIRIDrug
Also called ZALTRAP-FOLFIRI
Aflibercept-FOLFIRI
Aflibercept-mFOLFIRI3Drug
Also called ZALTRAP- mFOLFIRI3
Aflibercept-mFOLFIRI3

Study groups in NCT04392479
Study group	Role	What they receive
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 Receives: 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 Receives: Drug: Aflibercept-mFOLFIRI3

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 2 months

Secondary outcomes (9)

Disease control rate (DCR)
The disease control rate is the sum of patients with tumor response (either CR or PR) or stabilization (SD) as best response.
Measured: 2 months
Early response rate
The early response rate will be evaluated at the first tumor evaluation at 8 weeks (+/- 1 week).
Measured: 2 months
Progression-free survival (PFS)
PFS is defined as the time interval from randomization to the date of first documented disease progression or death from any cause, whichever occurs first. Alive patients without progression will be censored at the last tumor assessment, either during study treatment period or during follow-up period.
Measured: 2 months
Overall survival (OS)
OS is defined as the time interval from randomization to the date of death from any cause. Alive patients will be censored at the last date known to be alive, either during study treatment period or during follow-up period. Survival status will be assessed by telephone, ordinary visits, hospital records or other means found suitable until death or the end of the study, whichever occurs first. Information regarding post-study anti-cancer therapies will be collected if new treatment is initiated.
Measured: 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
Salvage surgery rate (%) corresponding to the number of patients amenable to surgery of metastasis during study treatment. The number of patients with R0 or R1 resection will be evaluated.
Measured: 2 months
Pathological response rate
The pathological tumor response will be assessed in patients having primary and/or metastasis resection using Tumor Regression Grade (TRG), modified TRG and Blazer grade. (Rubbia-Brandt L et al, Ann Oncol 2007 ; Blazer 3rd DG et al, J Clin Oncol 2008)
Measured: 2 months
Tolerance
frequency of AEs and SAEs per patient and per cycle of treatment using NCI CTCAE v5.0.
Measured: 2 weeks
HRQoL
The time until definitive HRQoL score deterioration (TUDD), (Bonnetain F et al, Eur J Cancer 2010) The survival without HRQoL deterioration-free survival (QFS). HRQoL will be assessed with EORTC QLQ-C30 questionnaire
Measured: 2 months
Exploratory biomarkers
Blood : (PlGF, VEGF-A, VEGF-B, VEGF-C, VEGF-D, sVEGFR1, sVEGFR2, sVEGFR3, Ang2, sTie2, Syndecan) .Exosomal biomarkers assessments (CEA, HSP70, VEGFR-2)
Tumor: Analyses will be performed according to the knowledge on potential markers at that time
Measured: 2 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

2 Sep 2020Jun 2024

First posted18 May 2020
Study start2 Sep 2020
Primary completion15 Jun 2023
Study completionJun 2024 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (19)Papers the sponsor has linked to this study.
Other trials for Cancer ColorectalStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 202 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04392479
Sponsor's protocol ID: FBH-002
Acronym: TWICE-IRI
Status last verified: Oct 2023
First submitted: 13 May 2020
Last updated: 23 Oct 2023
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

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.
PubMed 30207593
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.
PubMed 14657227
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.
PubMed 7577042
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.
PubMed 22949147
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.
PubMed 20921462
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.
PubMed 25877855
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-#.
PubMed 9398054
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.
PubMed 9771954
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.
PubMed 10674003
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.
PubMed 11481350
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.
PubMed 12796595
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.
PubMed 16622455
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.
PubMed 19153116
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.
PubMed 26806397
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.
PubMed 30254966

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 23 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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.
ClinicalTrials.gov ID: NCT04392479
Acronym / sponsor ID: TWICE-IRI / FBH-002
Conditions: Cancer Colorectal, Metastasis
Keywords: Aflibercept
Phase: Phase 3
Study type: Interventional
Recruitment status: Unknown status
Enrolment: 202 participants (estimated)
Lead sponsor: Hôpital Franco-Britannique-Fondation Cognacq-JayUniversity, hospital or other
Collaborators: Fondation ARCAD
Study start: 2 Sep 2020 (actual)
Primary completion: 15 Jun 2023 (actual)
Study completion: Jun 2024 (estimated)
First posted: 18 May 2020 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Detailed description

Study Objectives

Primary:

Secondary:

To evaluate disease control rate (DRC) and Early Response Rate (ERR)
To evaluate progression-free survival (PFS) and overall survival (OS),
to evaluate the conversion rate to locoregional therapy, surgery of metastasis, the quality of resection (R0, R1, R2) and the pathological response in patients with resected metastatic disease,
To assess the impact on health-related quality of life (HRQOL) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30),
To assess Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) on using the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 5.0).

Exploratory:

To assess the impact on selected circulating biomarkers (angiogenic and exosomal)
To assess the impact on selected tumor biomarkers

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Aflibercept-FOLFIRI (arm 1)	Active comparator	Drug: Aflibercept-FOLFIRI* 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
Aflibercept-mFOLFIRI3 (arm 2)	Experimental	Drug: Aflibercept-mFOLFIRI3* 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

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (22 listed)

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,

Key exclusion criteria (22 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Aflibercept-FOLFIRIAlso: ZALTRAP-FOLFIRIAflibercept-FOLFIRI	Drug	Aflibercept-FOLFIRI (arm 1)
Aflibercept-mFOLFIRI3Also: ZALTRAP- mFOLFIRI3Aflibercept-mFOLFIRI3	Drug	Aflibercept-mFOLFIRI3 (arm 2)

Primary outcome

Overall response rate (ORR).
Time frame: 2 months
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.

9 secondary outcomes

Disease control rate (DCR)
Time frame: 2 months
Early response rate
Time frame: 2 months
Progression-free survival (PFS)
Time frame: 2 months
Overall survival (OS)
Time frame: 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
Time frame: 2 months
Pathological response rate
Time frame: 2 months
Tolerance
Time frame: 2 weeks
HRQoL
Time frame: 2 months
Exploratory biomarkers
Time frame: 2 months

Results and safety

Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2023.
Background: PubMed 30207593Bray 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.
Background: PubMed 14657227Tournigand 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.
Background: PubMed 7577042Jolivet 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.
Background: PubMed 22949147Van 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.
Background: PubMed 20921462Peeters 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.
Background: PubMed 25877855Tabernero 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.
Background: PubMed 9398054Guichard 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-#.
Background: PubMed 9771954Mullany 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.
Background: PubMed 10674003Mans 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.
Background: PubMed 11481350Falcone 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.
Background: PubMed 12796595Mabro 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.
Background: PubMed 16622455Mabro 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.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Benoist CHIBAUDEL, MD principal investigator

Franco-British Hospital GCS IHFB Cognacq-Jay

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Aflibercept-FOLFIRI and Aflibercept-mFOLFIRI3 in people with Cancer Colorectal and Metastasis, run by Hôpital Franco-Britannique-Fondation Cognacq-Jay at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 23 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall response rate (ORR). (time frame: 2 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04392479, which also lists 19 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Oct 2023.