AzTrials
AzTrials

Metastatic Colorectal CancerPhase 1/2NCT04689347

5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.

A Phase 1/2 study testing Bevacizumab, Irinotecan and Leucovorin in people with Metastatic Colorectal Cancer, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 3 sites in Italy.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer (mCRC) including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved survival. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Metastatic Colorectal Cancer
What is being tested?
Bevacizumab, Irinotecan and Leucovorin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
27 participants
Where
3 sitesItaly
Study dates
1 Jan 2021to 31 Jan 2027
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

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 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically confirmed metastatic adenocarcinoma of the colon and/or rectum.
  • Confirmed MGMT promoter methylation by PSQ (> 5%) and absent MGMT expression by immunohistochemistry.
  • Locally assessed pMMR or MSS status.
  • Written informed consent obtained prior to any study procedures.
  • Availability of archival tumor tissue (primary tumor and metastases or at least one of the two) for confirmation of MGMT, MMR/MSI status and biomarker analyses.
  • Availability of blood sample for biomarker analysis.
Show all 19Show fewer
  • Metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
  • At least one measurable lesion according to RECIST 1.1.
  • Age ≥ 18 and less or equal than 75 years.
  • ECOG PS ≤ 1 if patient < 70 years old; ECOG PS 0 if patient 70-75 years old.
  • Life expectancy of at least 12 weeks.
  • Previous (neo)adjuvant fluoropyrimidine or fluoropyrimidine plus oxaliplatin chemotherapy allowed only if more than 6 months elapsed between the end of (neo)adjuvant therapy and first evidence of disease relapse.
  • Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hemoglobin ≥ 9 g/dl.
  • Total bilirubin ≤1.5 fold the upper-normal limits (UNL), AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x UNL (or <5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases).
  • Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
  • Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of amenorrhea, a single FSH measurement is insufficient.
  • Male subjects with female partners of childbearing potential and female subjects of childbearing potential must be willing to use adequate contraception as approved be the Investigator (barrier contraceptive measure or oral contraception) as outlined in Section 7.6, starting with the screening visit and through 6 months after the last treatment dose. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  • Will and ability to comply with the protocol.
  • Is willing and able to provide an adequate archival tumor sample (FFPE) available for molecular screening and exploratory analyses. If the tumor block is not available, a minimum of 25 3-micron unstained sections on charged slides of tumor will be required.

Who cannot join

  • Requirement for treatment with any medicinal product that contraindicates the use of any of the study medications, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications.
  • Metastatic disease deemed R0 resectable upfront or after induction therapy by means of multidisciplinary team assessment.
  • Radiotherapy to any site within 4 weeks before the study.
  • Presence of one of the following: DPYD2a (c.1905+1G>A); DPYD13 (c.1679 T>G); DPYD D949V (c.2846 A>T); DPYD IVS10 (c.1129-5923 C>G).
  • Presence of one of the following UGT1A1 1(TA)6/UGT1A1 36(TA)5; UGT1A1 28(TA)7/UGT1A1 37(TA)8 (homozygous genotype).
  • In the dose escalation phase, untreated brain metastases or spinal cord compression or primary brain tumors; in the dose expansion phase, known history of brain metastases.
Show all 17Show fewer
  • History or evidence upon physical examination of central nervous system disease unless adequately treated.8. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
  • 9. Evidence of bleeding diathesis or coagulopathy. 10. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
  • 11. Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
  • 12. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
  • 13. Any previous venous thromboembolism ≥ NCI CTCAE Grade 4. 14. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment.
  • 15. Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer).
  • 16. Other co-existing malignancies or malignancies diagnosed within the last 3 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
  • 17. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
  • 18. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
  • 19. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
  • 20. Pregnant or lactating women.

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Filippo Pietrantonio, MD contact

+390223903807

filippo.pietrantonio@istitutotumori.mi.it

Federica Morano, MD contact

+390223903842

federica.morano@istitutotumori.mi.it

Italy3 sites, 3 recruiting

  • Fondazione IRCCS Istituto Nazionale dei Tumori

    Milan, Milan, 20133

    Filippo Pietrantonio, MD, +390223903807, filippo.pietrantonio@istitutotumori.mi.it

    Federica Morano, MD, +390223903842, federica.morano@istitutotumori.mi.it

    Recruiting

  • Istituto Oncologico Veneto IRCCS

    Padova, PD, 35128

    Rossana Intini, MD, 049 821 1111, rossana.intini@iov.veneto.it

    Recruiting

  • Ospedale Santa Chiara

    Pisa, PI, 56126

    Chiara Cremolini, MD, 050.992111, chiaracremolini@gmail.com

    Recruiting

Other trials in Italy

About this study

Official title: Phase 1b/2 Trial of 5-fluorouracil, Leucovorin, Irinotecan in Combination With Temozolomide (FLIRT) and Bevacizumab for the First-line Treatment of Patients With MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.

An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer (mCRC) including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved survival. No biomarkers are available for predicting sensitivity/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs.

Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative/MGMT methylated and MSS cancers. Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines. Temozolomide could be regarded as a "targeted" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly super-selected mCRC patients.

Read more

Moving from this, the investigators designed this open-label, monocentric, phase 1b study evaluating the safety of the combination regimen 5-fluorouracil, leucovorin, irinotecan, temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC.

The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC. A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab. Upon completion of the phase 1b part, the phase 2 part of the study will start.

Read the detailed description

An upfront-intensified treatment combining all the three active cytotoxic agents in mCRC including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared to standard FOLFIRI and bevacizumab irrespective to RAS/BRAF status, at price of higher rate of specific toxicities. Advantages of an intensified regimen include: 1) exposure to all active available drugs, since more than 10-15% of patients would not receive any second-line therapy due to early performance status deterioration; 2) the chance of achieving a high rate (around 36%) of secondary R0/R1 resection of metastases in patients with liver-limited and initially unresectable liver metastases.

Furthermore, results from the phase 3 TRIBE2 study showed that the intensified upfront regimen FOLFOXIRI-bevacizumab followed by the pre-planned reintroduction of the same agents after progressive disease provided a statistically significant and clinically relevant survival benefit when compared with the pre-planned sequential administration of FOLFOX-bevacizumab and FOLFIRI-bevacizumab in unresectable patients with mCRC. Therefore, FOLFOXIRI-bevacizumab regimen is recommended by all major guidelines as one of the possible upfront treatment options for mCRC, and is used in the clinical practice mainly for patients with highly aggressive disease (such as those with right sided and/or RAS or BRAF mutated). Notably, since no biomarkers are available for predicting sensitivity/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs.

MGMT promoter methylation is found in about 40% of colorectal tumors. MGMT deficiency impairs DNA repair following administration of several alkylating agents, including temozolomide. Temozolomide has limited single-agent activity (around 10%) in patients with pretreated MGMT methylated mCRC. Promising activity has been reported for temozolomide in combination with the potentially synergic drug irinotecan (TEMIRI regimen) in clinically and molecularly selected patients. In a recent phase 2 randomized trial, capecitabine in combination with temozolomide (CAPTEM regimen) displayed similar activity and efficacy with respect to standard FOLFIRI as second-line therapy for MGMT methylated RAS mutated mCRC.

Heterogeneity of MGMT promoter methylation and residual MGMT protein expression might account for lack of activity of temozolomide in patients with MGMT promoter methylation assessed by means of a qualitative-only assay, i.e. methylation-specific PCR (MSP), which has been used as selection assay for patients' enrollment in published trials. Exploratory analyses have consistently shown the role of quantitative assessment of MGMT promoter methylation by means of digital PCR (methylBEAMing) and MGMT protein expression by immunohistochemistry (IHC) as potential predictive factors in mCRC patients treated with temozolomide. In the randomized phase 2 CAPTEM versus FOLFIRI second-line trial, patients with retained MGMT positivity by IHC had poorer outcomes in terms of PFS, OS and disease control rate (DCR: interaction test with arm: P=0.028). Any residual MGMT protein expression has been associated with lack of response to temozolomide across different trials, further supporting the restriction of temozolomide-based therapies for patients with MGMT IHC negativity coupled with gene methylation (MGMT silencing).

Mismatch repair deficiency/microsatellite instability (MSI) has been linked to innate resistance to several alkylating chemotherapeutic agents, including temozolomide, since cytotoxicity of these agents strictly relies on functional mismatch repair. Therefore, patients with MSI-high mCRC are excluded from temozolomide-based therapy.

Temozolomide could be regarded as a "targeted" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly hyperselected mCRC patients.

Moving from this rationale the investigators designed this phase 1b trial assessing safety, recommended dose and preliminary activity of 5-fluoruracil, irinotecan, temozolomide and bevacizumab (FLIRT-bevacizumab) as a biomarker-guided initial therapy for patients with MGMT silenced and MSS mCRC.

The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC.

A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab.

The MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity (DLT). When the MTD or maximum tested dose has been determined or reached, the RP2D to be tested in a future phase II trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. At least 6 patients should be treated at the RD during the dose escalation.

The treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FU/LV-bevacizumab administered every 14 days in combination with per os temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period. Patients will undergo tumor assessment at baseline and every 8 ± 1 weeks until confirmed disease progression, unacceptable toxicity, withdrawal of consent, death, whichever occurs first. The treatment will continue until progressive disease, unacceptable toxicities, or consent withdrawal.

The phase 1b part of the study has been completed and the RP2D of temozolomide is 150 mg/sqm on days 1-5 every 28 days. The phase 2 part is ongoing.

Being tested
Bevacizumab, Irinotecan, Leucovorin, 5Fluorouracil, Temozolomide
Keywords
Temozolomide, MGMT, microsatellite stable, First-line, Phase 1, Colorectal cancer
Medical subject headings
Colorectal Neoplasms

What participants receive

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

  • BevacizumabDrug

    Bevacizumab 5 mg/kg intravenous infusion every 2 weeks

  • IrinotecanDrug

    irinotecan 165 mg/sqm intravenous infusion every 2 weeks

  • LeucovorinDrug

    leucovorin 200 mg/sqm intravenous infusion every 2 weeks

  • 5FluorouracilDrug

    48-hours continuous intravenous infusion of 5-fluorouracil (5-FU) 3200 mg/sqm every 2 weeks

  • TemozolomideDrug

    Oral temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days. (75 mg/sqm; 100 mg/sqm; 125 mg/sqm or 150 mg/sqm)

Study groups in NCT04689347
Study groupRoleWhat they receive
FLIRT-bevacizumabExperimentalBevacizumab intravenous infusion (IV), irinotecan IV, leucovorin (LV) IV, 48-hours continuous intravenous infusion of 5-fluorouracil (5-FU), given every 14 days, in combination with oral (PO) temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days. The treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FU/LV-bevacizumab administered every 14 days in combination with PO temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period. In the phase 2 patient will receive the same treatment of the phase 1b with temozolomide at the RP2D (150 mg/sqm)
Receives: Drug: Bevacizumab; Drug: Irinotecan; Drug: Leucovorin; Drug: 5Fluorouracil; Drug: Temozolomide

What is being measured

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

  1. (Phase 1b) safety and to determine the recommended phase 2 dose of the combination of FLIRT- bevacizumab in patients with MGMT silenced and MSS mCRC, previously untreated for advanced disease. (Phase 2) efficacy of FLIRT/bev

    (phase 1b) The RD to be tested in a future phase 2 trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. he MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity. At least 6 patients should be treated at the RD during the dose escalation.

    (phase 2) an overall sample size of 27 patients achieves an 80% power to detect the probability to increase 9-month PFS rate to 55% with a one-sided α level of 0.1 by the combination of temozolomide at the RP2D in combination with irinotecan, 5-fluorouracil and bevacizumab. The null hypothesis will be rejected if at least 14 patients are free of disease progression at 9 months.

    Measured: 24 months

Secondary outcomes (4)

  1. ORR obtained by FLIRT bevacizumab

    To assess ORR per RECIST version 1.1

    Measured: 24 months

  2. Quality of life as assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

    EORTC QLQ-C30 administered every 8 weeks

    Measured: 24 months

  3. Quality of life as assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29)

    EORTC QLQ-CR29 administered every 8 weeks

    Measured: 24 months

  4. Quality of life as assessed using the Euro Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L)

    EQ-5D-5L administered every 8 weeks

    Measured: 24 months

Timeline

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

  1. First posted30 Dec 2020
  2. Study start1 Jan 2021
  3. Primary completion30 Apr 2026 (estimated)
  4. Study completion31 Jan 2027 (estimated)

Resources

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Model description
A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab. The MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity (DLT). When the MTD or maximum tested dose has been determined or reached, the RP2D to be tested in a future phase II trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. At least 6 patients should be treated at the RD during the dose escalation. Regarding the expansion part of the study, considering a 9-month PFS rate of 35% in patients receiving FOLFIRI plus bevacizumab (which has been shown in the RAS mutated subgroup of TRIBE trial and considering that MGMT methylation is strongly associated with RAS mutations), an overall sample size of 27 patients achieves an 80% power to detect the probability to increase 9-month PFS rate to 55% with a one-sided α level of 0.1 by the combination of temozolomide at
Masking
None (open label)
Enrolment
27 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04689347
Sponsor's protocol ID
INT 151/20
Status last verified
Sep 2025
First submitted
22 Dec 2020
Last updated
12 Jan 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K, Xu RH, Kim TW, Ismail F, Tan IB, Yeh KH, Grothey A, Zhang S, Ahn JB, Mastura MY, Chong D, Chen LT, Kopetz S, Eguchi-Nakajima T, Ebi H, Ohtsu A, Cervantes A, Muro K, Tabernero J, Minami H, Ciardiello F, Douillard JY. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol. 2018 Jan 1;29(1):44-70. doi: 10.1093/annonc/mdx738.

    PubMed 29155929

  • 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

  • de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. doi: 10.1200/JCO.2000.18.16.2938.

    PubMed 10944126

  • Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. doi: 10.1016/s0140-6736(00)02034-1.

    PubMed 10744089

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.

    PubMed 15175435

  • Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, von Moos R, Vieitez JM, Bouche O, Borg C, Steffens CC, Alonso-Orduna V, Schlichting C, Reyes-Rivera I, Bendahmane B, Andre T, Kubicka S; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37. doi: 10.1016/S1470-2045(12)70477-1. Epub 2012 Nov 16.

    PubMed 23168366

  • Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015 Jan;26(1):13-21. doi: 10.1093/annonc/mdu378. Epub 2014 Aug 12.

    PubMed 25115304

  • Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. Eur J Cancer. 2017 Jan;70:87-98. doi: 10.1016/j.ejca.2016.10.007. Epub 2016 Nov 29.

    PubMed 27907852

  • Falcone A, Masi G, Allegrini G, Danesi R, Pfanner E, Brunetti IM, Di Paolo A, Cupini S, Del Tacca M, Conte P. Biweekly chemotherapy with oxaliplatin, irinotecan, infusional Fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer. J Clin Oncol. 2002 Oct 1;20(19):4006-14. doi: 10.1200/JCO.2002.12.075.

    PubMed 12351598

  • Masi G, Allegrini G, Cupini S, Marcucci L, Cerri E, Brunetti I, Fontana E, Ricci S, Andreuccetti M, Falcone A. First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule. Ann Oncol. 2004 Dec;15(12):1766-72. doi: 10.1093/annonc/mdh470.

    PubMed 15550581

  • Masi G, Loupakis F, Salvatore L, Fornaro L, Cremolini C, Cupini S, Ciarlo A, Del Monte F, Cortesi E, Amoroso D, Granetto C, Fontanini G, Sensi E, Lupi C, Andreuccetti M, Falcone A. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010 Sep;11(9):845-52. doi: 10.1016/S1470-2045(10)70175-3. Epub 2010 Aug 9.

    PubMed 20702138

  • Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108.

    PubMed 25337750

  • Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004 Apr 1;22(7):1209-14. doi: 10.1200/JCO.2004.11.037.

    PubMed 15051767

  • Cremolini C, Casagrande M, Loupakis F, Aprile G, Bergamo F, Masi G, Moretto R R, Pietrantonio F, Marmorino F, Zucchelli G, Tomasello G, Tonini G, Allegrini G, Granetto C, Ferrari L, Urbani L, Cillo U, Pilati P, Sensi E, Pellegrinelli A, Milione M, Fontanini G, Falcone A. Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest. Eur J Cancer. 2017 Mar;73:74-84. doi: 10.1016/j.ejca.2016.10.028. Epub 2016 Dec 13.

    PubMed 27986363

  • Pietrantonio F, Cotsoglou C, Fuca G, Lo Vullo S, Nichetti F, Milione M, Coppa J, Vaiani M, Alessi A, Prisciandaro M, Droz-Dit Busset M, Morano F, Corallo S, Lazzati S, Antista M, Mennitto A, Randon G, Raimondi A, Belfiore A, Padovano B, Perrone F, Mariani L, Di Bartolomeo M, de Braud F, Mazzaferro V. Perioperative Bevacizumab-based Triplet Chemotherapy in Patients With Potentially Resectable Colorectal Cancer Liver Metastases. Clin Colorectal Cancer. 2019 Mar;18(1):34-43.e6. doi: 10.1016/j.clcc.2018.11.004. Epub 2018 Nov 24.

    PubMed 30558859

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Bevacizumab, Irinotecan and Leucovorin in people with Metastatic Colorectal Cancer, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 3 sites in Italy.

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 19 inclusion and 17 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: looking for participants now, as of the sponsor's last update on 12 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Italy. 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 combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

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

Contact Filippo Pietrantonio, MD (+390223903807, filippo.pietrantonio@istitutotumori.mi.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

(Phase 1b) safety and to determine the recommended phase 2 dose of the combination of FLIRT- bevacizumab in patients with MGMT silenced and MSS mCRC, previously untreated for advanced disease. (Phase 2) efficacy of FLIRT/bev (time frame: 24 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 NCT04689347, which also lists 41 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 12 Jan 2026.

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