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Combination treatment for metastatic colorectal cancer patients

Phase III Randomized Study of FOLFOXIRI Plus Bevacizumab and Atezolizumab Versus FOLFOXIRI Plus Bevacizumab as First-Line Treatment of Unresectable pMMR and Immunoscore IC-High Metastatic Colorectal Cancer Patients

Phase 3 Interventional Gruppo Oncologico del Nord-Ovest · NCT06733038

This study is testing if adding Atezolizumab to the usual treatment for patients with advanced colorectal cancer can help them live longer without their cancer getting worse.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment238 (estimated)
Ages18 Years to 75 Years
SexAll
SponsorGruppo Oncologico del Nord-Ovest Academic / other
Drugs / interventionsbevacizumab, atezolizumab, denosumab, chemotherapy, methotrexate, cyclophosphamide, prednisone
Locations24 sites (Brescia, BS and 23 other locations)
Trial IDNCT06733038 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness of adding Atezolizumab to the standard treatment of FOLFOXIRI plus bevacizumab for patients with pMMR and Immunoscore IC-high metastatic colorectal cancer. It is a phase III, open-label, multicenter, randomized trial where participants will receive either the standard treatment or the combination treatment for up to 8 cycles, followed by maintenance therapy. The study aims to assess progression-free survival as the primary outcome measure, with stratification based on performance status, tumor location, and liver metastases.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18-75 with unresectable, previously untreated pMMR and Immunoscore IC-high metastatic colorectal cancer.

Not a fit: Patients with resectable metastatic colorectal cancer or those with different mismatch repair statuses may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve progression-free survival for patients with a specific type of metastatic colorectal cancer.

How similar studies have performed: Other studies have shown promising results with similar immunotherapy approaches in colorectal cancer, suggesting potential for success in this trial.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* 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;
* 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 following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 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 12 months of amenorrhea, a single FSH measurement is insufficient;
* Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception) and outlined in "Section 6.5 - Contraception", starting with the first dose of study therapy through 6 months after the last dose of bevacizumab and fluorouracil and within 5 months after the last dose of atezolizumab.
* Females of childbearing potential must have a negative blood pregnancy test at the baseline visit (i.e., performed maximum 7 days before the treatment start);
* Will and ability to comply with the protocol;
* Written informed consent to study procedures.

Exclusion Criteria:

* 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;
* Active infection requiring antibiotics at the time of initiation of study treatment;
* Any previous venous thromboembolism ≥ NCI CTCAE Grade 4;
* History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment;
* Current or recent (within 10 days prior to study treatment start) ongoing treatment with full-dose anticoagulants for therapeutic purposes.
* Chronic, daily treatment with high-dose aspirin (\>325 mg/day);
* 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 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study;
* Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment;
* Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication;
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last dose of bevacizumab, fluorouracil and within 5 months after the last dose of atezolizumab;
* History of autoimmune disease;
* History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan;
* Positive test for human immunodeficiency virus (HIV);
* Active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test prior to randomization) or hepatitis C;
* Active tuberculosis;
* Prior allogenic bone marrow transplantation or solid organ transplant;
* Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor \[TNF\] agents) within 2 weeks prior to start of study treatment, or requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed;
* Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of the atezolizumab formulation;
* Administration of a live, attenuated vaccine within 4 weeks prior to start of study treatment or anticipation that such a live attenuated vaccine will be required during the study;
* Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of study treatment; • If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment such as (but not limited to) bisphosphonates, while receiving atezolizumab.

Where this trial is running

Brescia, BS and 23 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Colorectal CanceratezolizumabFOLFIXIRI/bevacizumabmetastatic colorectal cancerpMMR/MSSIMMUSCORE IC-Highfirst line
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.