FOLFOXIRI Plus Bevacizumab With or Without Atezolizumab as 1st Line Treatment of pMMR and IS IC-High Metastatic Colorectal Cancer Patients.

NCT06733038 | Recruiting Phase 3

• 1 other identifier: AtezoTRIBE2
• Study Type: interventional
• Target: 238
• Locations: 1 country
• Sites: 24

Brief Summary

The aim of this study is to evaluate the efficacy of the addition of Atezolizumab to FOLFOXIRI plus bevacizumab as first line treatment of patients with pMMR and Immunoscore IC-high metastatic colorectal cancer in terms of Progression Free Survival (PFS).

Conditions

Colorectal Cancer

Keywords

atezolizumab; FOLFIXIRI/bevacizumab; metastatic colorectal cancer; pMMR/MSS; IMMUSCORE IC-High; first line

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  PFS is defined as the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis. Alive patients having no tumor assessments after baseline will have time to event censored on the date of randomization.

  24 months

Secondary Outcomes (12)

• Overall Toxicity Rate

  24 months

• Toxicity Rate

  24 months

• Objective Response Rate

  24 months

• Immuno-related Objective Response Rate

  24 months

• Early Objective Response Rate

  up to 2 months from randomization

Study Arms (2)

Arm A - FOLFOXIRI plus bevacizumab

ACTIVE COMPARATOR

Every 2 weeks for a maximum of 8 cycles: * Bevacizumab 5 mg/kg iv 90 minutes at cycle 1 (if well tolerated, it is administered over 60 minutes at cycle 2, and over 30 minutes at cycle 3) day 1, followed by * Irinotecan 165 mg/sqm iv over 60 minutes day 1, followed by * Oxaliplatin 85 mg/sqm iv over 2 hours day 1, in two-way with * L-Leucovorin 200 mg/sqm iv over 2 hours day 1, followed by * 5-fluorouracil 3200 mg/sqm 48 h-continuous infusion, starting on day 1. If no progression occurs during FOLFOXIRI plus bev, patients will receive maintenance 5-FU/LV plus bev at the same dose used at the last cycle of the induction treatment. 5-FU/LV plus bev will be repeated biweekly until disease progression, unacceptable toxicity or patient's refusal.

Drug: Bevacizumab; Drug: Irinotecan (CPT-11); Drug: Oxaliplatin; Drug: Leucovorin; Drug: Fluorouracil (5-FU)

Arm B - FOLFOXIRI plus bevacizumab plus atezolizumab

EXPERIMENTAL

Every 2 weeks for a maximum of 8 cycles: * Atezolizumab 840 mg iv over 30 minutes (60 minutes at first infusion) day 1 followed by * Bevacizumab 5 mg/kg iv over 90 minutes at cycle 1 (if well tolerated, it is administered over 60 minutes at cycle 2, and over 30 minutes at cycle 3) day 1 followed by * Irinotecan 165 mg/sqm iv over 60 minutes day 1, followed by * Oxaliplatin 85 mg/sqm iv over 2 hours day 1, in two-way with * L-Leucovorin 200 mg/sqm iv over 2 hours day 1, followed by * 5-fluorouracil 3200 mg/sqm 48 h-continuous infusion, starting on day 1. If no progression occurs during FOLFOXIRI plus bev plus atezolizumab, patients will receive maintenance 5-FU/LV plus bev plus atezolizumab at the same dose used at the last cycle of the induction treatment. 5-FU/LV plus bev plus atezolizumab will be repeated biweekly until disease progression, unacceptable toxicity or patient's refusal.

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Irinotecan (CPT-11); Drug: Oxaliplatin; Drug: Leucovorin; Drug: Fluorouracil (5-FU)

Interventions

Leucovorin DRUG

200 mg/sqm iv over 2 hours day 1

Arm A - FOLFOXIRI plus bevacizumab; Arm B - FOLFOXIRI plus bevacizumab plus atezolizumab

Atezolizumab DRUG

840 mg iv over 30 minutes (60 minutes at first infusion) day 1

Arm B - FOLFOXIRI plus bevacizumab plus atezolizumab

Bevacizumab DRUG

5 mg/kg iv over 90 minutes at cycle 1 (if well tolerated, it is administered over 60 minutes at cycle 2, and over 30 minutes at cycle 3) day 1

Arm A - FOLFOXIRI plus bevacizumab; Arm B - FOLFOXIRI plus bevacizumab plus atezolizumab

Irinotecan (CPT-11) DRUG

165 mg/sqm iv over 60 minutes day 1

Arm A - FOLFOXIRI plus bevacizumab; Arm B - FOLFOXIRI plus bevacizumab plus atezolizumab

Oxaliplatin DRUG

85 mg/sqm iv over 2 hours day 1

Arm A - FOLFOXIRI plus bevacizumab; Arm B - FOLFOXIRI plus bevacizumab plus atezolizumab

Fluorouracil (5-FU) DRUG

3200 mg/sqm 48 h-continuous infusion, starting on day 1

Arm A - FOLFOXIRI plus bevacizumab; Arm B - FOLFOXIRI plus bevacizumab plus atezolizumab

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 proven diagnosis of colorectal cancer;
• Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease;
• Proficient mismatch repair (pMMR) status in tumour tissue (primary or metastatic), as determined by a local laboratory assay in a CLIA- or similarly certified;
• Immunoscore IC-high status in tumour tissue (primary or metastatic), as determined by a sponsor-defined central laboratory (HEGP, AP-HP, INSERM, France).
• At least one measurable lesion according to RECIST criteria (version 1.1);
• Availability of adequate tumour specimen (primary or metastatic);
• Male or female of 18-75 years of age;
• ECOG PS ≤ 2 if aged \< 71 years, ECOG PS = 0 if aged 71-75 years;
• Life expectancy of at least 12 weeks;
• Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse;
• Neutrophils \>1.5 x 109/L, Platelets \>100 x 109/L, Hb \>9 g/dl;
• Total bilirubin ≤1.5 times the upper-normal limits (UNL) of the normal values and AST (SGOT) and/or ALT (SGPT) \<2.5 x UNL (or \<5 x UNL in 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;
• INR or aPTT ≤1.5 x ULN. This applies only to patients who are not receiving therapeutic anticoagulation;
• Urine dipstick of proteinuria \<2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein/24 h;

You may not qualify if:

• Radiotherapy to any site within 4 weeks before the study;
• Previous adjuvant oxaliplatin-containing chemotherapy;
• Previous treatment with bevacizumab;
• Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents;
• Complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT);
• Untreated brain metastases or spinal cord compression or primary brain tumours;
• History or evidence upon physical examination of CNS disease unless adequately treated;
• History of haemoptysis ≥ 2 grade NCIC-CTG criteria within one month prior to screening;
• Active or untreated CNS metastases:
• Symptomatic peripheral neuropathy \> 2 grade NCIC-CTG criteria;
• Serious, non-healing wound, ulcer, or bone fracture;
• Evidence of bleeding diathesis or coagulopathy;
• Uncontrolled hypertension (SBP\>150 mmHg and/or DPB\>100 mmHg), or prior history of hypertensive crisis, or hypertensive encephalopathy ;
• Clinically significant (i.e., active) cardiovascular disease for example cerebrovascular accidents (within 6 months prior to study enrollment), myocardial infarction (within 6 months prior to study enrollment), 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;

Sponsors & Collaborators

• Hoffmann-La Roche: collaborator
• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (24)

Fondazione Poliambulanza, Istituto Ospedaliero

Brescia, BS, 25124, Italy

RECRUITING

Azienda Ospedaliero Universitaria Policlinico Rodolico - S. Marco

Catania, CT, 95123, Italy

RECRUITING

Istituto Romagnolo per lo Studio dei Tumori Dino Amadori

Meldola, FC, 47014, Italy

RECRUITING

Fondazione Casa Sollievo della Sofferenza

San Giovanni Rotondo, FG, 71013, Italy

RECRUITING

AOU Careggi

Florence, FI, 50134, Italy

RECRUITING

Azienda Ospedaliera Card. G. Panico

Tricase, LE, 73039, Italy

RECRUITING

Azienda USL Toscana Nord Ovest

Livorno, LI, 57124, Italy

RECRUITING

Ospedale San Luca

Lucca, LU, 55100, Italy

RECRUITING

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, MI, 20122, Italy

RECRUITING

Ospedale San Raffaele

Milan, MI, 20132, Italy

RECRUITING

Fondazione IRCCS INT - Milano

Milan, MI, 20133, Italy

RECRUITING

Azienda Ospedaliero Universitaria di Modena

Modena, MO, 41124, Italy

RECRUITING

Istituto Oncologico Veneto Irccs

Padua, PD, 35128, Italy

RECRUITING

IRCCS Centro di Riferimento Oncologico

Aviano, PN, 33081, Italy

RECRUITING

Nuovo Ospedale di Prato S. Stefano

Prato, PO, 59100, Italy

RECRUITING

Azienda USL della Romagna

Ravenna, RA, 48121, Italy

RECRUITING

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Roma, RM, 00168, Italy

RECRUITING

Azienda Sanitaria Universitaria Friuli Centrale

Udine, UD, 33100, Italy

RECRUITING

ASL di Viterbo

Viterbo, VT, 01100, Italy

RECRUITING

Azienda Ospedaliera Universitaria Luigi Vanvitelli

Naples, 80131, Italy

RECRUITING

IRCCS Istituto Nazionale Tumori "Fondazione Giovanni Pascale"

Naples, 80131, Italy

RECRUITING

Azienda Usl di Piacenza

Piacenza, 29121, Italy

RECRUITING

U.O. Oncologia Medica 2 Universitaria - Azienda Ospedaliero-Universitaria Pisana Dipartimento di Ricerca Traslazionale e Nuove Tecnologie - University of Pisa

Pisa, 56126, Italy

RECRUITING

Policlinico Universitario Tor Vergata

Rome, 00133, Italy

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

atezolizumab; Bevacizumab; Irinotecan; Oxaliplatin; Leucovorin; Fluorouracil

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; Coordination Complexes; Organic Chemicals; 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

Study Officials

• Carlotta Antoniotti, MD, PhD

  Department of Translational Research and New Technologies in Medicine and Surgery - University of Pisa

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Carlotta Antoniotti, MD, PhD

CONTACT

+39050992192; carlotta.antoniotti@unipi.it

Laura Delliponti

CONTACT

+39050992192; atezotribe2@gmail.com

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: December 2, 2024
• First Posted: December 13, 2024
• Study Start: November 15, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2029
• Last Updated: December 8, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (24)