Clinical trial NCT06733038: FOLFOXIRI Plus Bevacizumab With or Without Atezolizumab as 1st Line Treatment of pMMR and IS IC-High Metastatic Colorectal Cancer Patients.
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: atezolizumab
FOLFIXIRI/bevacizumab
metastatic colorectal cancer
pMMR/MSS
IMMUSCORE IC-High
first line
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2024-12-13
Enrollment: 238
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed description: This is a prospective, open-label, multicenter phase III randomized trial in which patients with initially unresectable, previously untreated pMMR and Immunoscore IC-high mCRC will be randomized in a 1:1 ratio to receive induction treatment with FOLFOXIRI plus bevacizumab up to 8 cycles followed by maintenance with 5-FU/LV plus bevacizumab until disease progression, unacceptable toxicity or patient's refusal (arm A) or FOLFOXIRI plus bevacizumab plus atezolizumab up to 8 cycles followed by maintenance with 5-FU/LV plus bevacizumab plus atezolizumab until disease progression, unacceptable toxicity or patient's refusal (arm B).

Stratification factors will be ECOG Performance Status (0 versus 1, 2), primary tumour location (right versus left/rectum) and liver metastases (yes versus no).

The second- and subsequent lines of treatment will be at investigators' choice.

Eligibility 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 24 months
Secondary outcomes:
measure: Overall Toxicity Rate
timeFrame: 24 months
measure: Toxicity Rate
timeFrame: 24 months
measure: Objective Response Rate
timeFrame: 24 months
measure: Immuno-related Objective Response Rate
timeFrame: 24 months
measure: Early Objective Response Rate
timeFrame: up to 2 months from randomization
measure: Depth of Response
timeFrame: 24 months
measure: R0 Resection Rate
timeFrame: 24 months
measure: Duration of Response
timeFrame: 24 months
measure: Overall survival
timeFrame: 48 months
measure: Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
timeFrame: Questionnaires will be administered at baseline, every 4 weeks during induction treatment, every 8 weeks thereafter, at the time of evidence of disease progression, after 30 days following end of study treatment/disease progression.
measure: Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Module for Colorectal cancer 29 (EORTC QLQ-CR29).
timeFrame: Questionnaires will be administered at baseline, every 4 weeks during induction treatment, every 8 weeks thereafter, at the time of evidence of disease progression, after 30 days following end of study treatment/disease progression.
measure: Time To Deterioration in Quality of Life (TTD)
timeFrame: 24 months
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Fondazione Poliambulanza, Istituto Ospedaliero
state: BS
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico Rodolico - S. Marco
state: CT
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori
state: FC
city: San Giovanni Rotondo
country: Italy
facility: Fondazione Casa Sollievo della Sofferenza
state: FG
city: Florence
country: Italy
facility: AOU Careggi
state: FI
city: Tricase
country: Italy
facility: Azienda Ospedaliera Card. G. Panico
state: LE
city: Lucca
country: Italy
facility: Ospedale San Luca
state: LU
city: Milan
country: Italy
facility: Ospedale San Raffaele
state: MI
city: Milan
country: Italy
facility: Fondazione IRCCS INT - Milano
state: MI
city: Padova
country: Italy
facility: Istituto Oncologico Veneto Irccs
state: PD
city: Aviano
country: Italy
facility: IRCCS Centro di Riferimento Oncologico
state: PN
city: Prato
country: Italy
facility: Nuovo Ospedale di Prato S. Stefano
state: PO
city: Ravenna
country: Italy
facility: Azienda USL della Romagna
state: RA
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
state: RM
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Friuli Centrale
state: UD
city: Naples
country: Italy
facility: Azienda Ospedaliera Universitaria Luigi Vanvitelli
city: Piacenza
country: Italy
facility: Azienda Usl di Piacenza
city: Pisa
country: Italy
facility: U.O. Oncologia Medica 2 Universitaria - Azienda Ospedaliero-Universitaria Pisana Dipartimento di Ricerca Traslazionale e Nuove Tecnologie - University of Pisa
city: Rome
country: Italy
facility: Policlinico Universitario Tor Vergata
Study officials:
affiliation: Department of Translational Research and New Technologies in Medicine and Surgery - University of Pisa
name: Carlotta Antoniotti, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: