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

NCT04689347 | Recruiting Phase 1

• 1 other identifier: INT 151/20
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 3

Brief 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. 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. 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.

Conditions

Metastatic Colorectal Cancer

Keywords

Temozolomide; MGMT; microsatellite stable; First-line; Phase 1; Colorectal cancer

Outcome Measures

Primary Outcomes (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.

  24 months

Secondary Outcomes (4)

• ORR obtained by FLIRT bevacizumab

  24 months

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

  24 months

• 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)

  24 months

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

  24 months

Other Outcomes (4)

• OS of FLIRT bevacizumab (phase 2) - secondary endpoint for phase 2

  24 months

• Evaluate tumor biomarkers in archival tumor tissue

  24 months

• Evaluate plasma biomarkers in longitudinal blood samples (plasma and PBMCs)

  24 months

Study Arms (1)

FLIRT-bevacizumab

EXPERIMENTAL

Bevacizumab 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)

Drug: Bevacizumab; Drug: Irinotecan; Drug: Leucovorin; Drug: 5Fluorouracil; Drug: Temozolomide

Interventions

Bevacizumab DRUG

Bevacizumab 5 mg/kg intravenous infusion every 2 weeks

FLIRT-bevacizumab

Irinotecan DRUG

irinotecan 165 mg/sqm intravenous infusion every 2 weeks

FLIRT-bevacizumab

Leucovorin DRUG

leucovorin 200 mg/sqm intravenous infusion every 2 weeks

FLIRT-bevacizumab

5Fluorouracil DRUG

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

FLIRT-bevacizumab

Temozolomide DRUG

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)

FLIRT-bevacizumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.
• \. Evidence of bleeding diathesis or coagulopathy. 10. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
• \. 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.
• \. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
• \. 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.
• \. Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer).
• \. 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.
• \. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
• \. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead

Study Sites (3)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Milan, 20133, Italy

RECRUITING

Istituto Oncologico Veneto IRCCS

Padua, PD, 35128, Italy

RECRUITING

Ospedale Santa Chiara

Pisa, PI, 56126, Italy

RECRUITING

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• Germano G, Lamba S, Rospo G, Barault L, Magri A, Maione F, Russo M, Crisafulli G, Bartolini A, Lerda G, Siravegna G, Mussolin B, Frapolli R, Montone M, Morano F, de Braud F, Amirouchene-Angelozzi N, Marsoni S, D'Incalci M, Orlandi A, Giraudo E, Sartore-Bianchi A, Siena S, Pietrantonio F, Di Nicolantonio F, Bardelli A. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature. 2017 Dec 7;552(7683):116-120. doi: 10.1038/nature24673. Epub 2017 Nov 29.

  PMID: 29186113 BACKGROUND

• Lu Y, Zhao Z, Wang J, Lv W, Lu L, Fu W, Li W. Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: A meta-analysis. Medicine (Baltimore). 2018 Oct;97(41):e12784. doi: 10.1097/MD.0000000000012784.

  PMID: 30313101 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab; Irinotecan; Leucovorin; Fluorouracil; Temozolomide

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles

Study Officials

• Filippo Pietrantonio, MD

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Filippo Pietrantonio, MD

CONTACT

+390223903807; filippo.pietrantonio@istitutotumori.mi.it

Federica Morano, MD

CONTACT

+390223903842; federica.morano@istitutotumori.mi.it

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: December 22, 2020
• First Posted: December 30, 2020
• Study Start: January 1, 2021
• Primary Completion: April 30, 2026
• Study Completion (Estimated): January 31, 2027
• Last Updated: January 12, 2026

Record last verified: 2025-09

Locations

IT (3)