FOLFOXIRI + Bev + Atezo vs FOLFOXIRI + Bev as First-line Treatment of Unresectable Metastatic Colorectal Cancer Patients

NCT03721653 | Completed Phase 2 DMC

• 1 other identifier: 2017-000977-35
• Study Type: interventional
• Target: 218
• Locations: 1 country
• Sites: 1

Brief Summary

The scope of this study is to evaluate the efficacy of the addition of atezolizumab to FOLFOXIRI plus bevacizumab as first line treatment of patients with metastatic colorectal cancer in terms of Progression Free Survival.

Conditions

Metastatic Colorectal Cancer

Keywords

FOLFOXIRI; Bevacizumab; Atezolizumab

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  Progression-free survival is defined as the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first.

  16 months

Secondary Outcomes (9)

• Overall toxicity rate

  24 months

• Toxicity rate

  24 months

• Objective response rate according to RECIST version 1.1 criteria (ORR)

  16 months

• Immuno-related objective response rate according to modified RECIST criteria (irORR)

  16 months

• Early Objective Response Rate (EOR)

  16 months

Study Arms (2)

FOLFOXIRI + Bevacizumab

ACTIVE COMPARATOR

(to be repeated every 2 weeks for a maximum of 8 cycles) Bevacizumab 5 mg/kg iv over 30 minutes 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 (to be repeated every 2 weeks for a maximum of 8 cycles) 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. The prosecution of bev until disease progression is recommended also if 5-FU is interrupted because of adverse events, patient's refusal or investigator's choice.

Drug: Bevacizumab; Drug: Irinotecan; Drug: Oxaliplatin; Drug: L-Leucovorin; Drug: 5-fluorouracil

FOLFOXIRI + Bevacizumab + Atezolizumab

EXPERIMENTAL

Atezolizumab 840 mg iv over 30 minutes(60 minutes at the first infusion) day 1 followed by Bevacizumab 5 mg/kg iv over 30 minutes 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 (to be repeated every 2 weeks for a maximum of 8 cycles) 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. The prosecution of bev and atezolizumab until disease progression is recommended also if 5-FU is interrupted because of adverse events, patient's refusal or investigator's choice.

Drug: Bevacizumab; Drug: Irinotecan; Drug: Oxaliplatin; Drug: L-Leucovorin; Drug: 5-fluorouracil; Drug: Atezolizumab

Interventions

Bevacizumab DRUG

5 mg/kg iv over 30 minutes day 1

FOLFOXIRI + Bevacizumab; FOLFOXIRI + Bevacizumab + Atezolizumab

Irinotecan DRUG

165 mg/sqm iv over 60 minutes day 1

FOLFOXIRI + Bevacizumab; FOLFOXIRI + Bevacizumab + Atezolizumab

Oxaliplatin DRUG

85 mg/sqm iv over 2 hours day 1

FOLFOXIRI + Bevacizumab; FOLFOXIRI + Bevacizumab + Atezolizumab

L-Leucovorin DRUG

200 mg/sqm iv over 2 hours day 1

FOLFOXIRI + Bevacizumab; FOLFOXIRI + Bevacizumab + Atezolizumab

5-fluorouracil DRUG

3200 mg/sqm 48 h-continuous infusion

FOLFOXIRI + Bevacizumab; FOLFOXIRI + Bevacizumab + Atezolizumab

Atezolizumab DRUG

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

FOLFOXIRI + Bevacizumab + 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:

• Written informed consent to study procedures
• Histologically proven diagnosis of colorectal cancer
• Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease
• At least one measurable lesion according to RECIST1.1 criteria
• Availability of a tumoral sample
• Male or female of 18-75 years of age
• ECOG PS \< or = 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, Hgb \>9 g/dl
• Total bilirubin 1.5 time the upper-normal limits (UNL) of the normal values and ASAT (SGOT) and/or ALAT (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 1.25 x UNL
• INR or aPTT ≤1.5 × ULN. Patients who are on therapeutic doses of anti-coagulants are eligible if they are on a stable dose of anti-coagulant for 28 days with stable INR and PTT values
• 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 hr
• Male subjects with female partners of childbearing potential must be willing to use adequate contraception as outlined in Section 5.5 - Contraception, starting with the first dose of study therapy through 6 months after the last dose of bevacizumab and within 5 months after the last dose of atezolizumab.

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
• Untreated brain metastases or spinal cord compression or primary brain tumours
• History or evidence upon physical examination of CNS disease unless adequately treated
• Hystory of haemoptysis ≥2 grade NCIC-CTG criteria within one month prior screening
• Active or untreated CNS metastases. Patients with a history of treated asymptomatic CNS metastases are eligible provided they meet all the following criteria:
• Measurable disease outside the CNS
• Only supratentorial or cerebellar metastases allowed (i.e. no metastases to midbrain, pons, medulla or spinal cord)
• No ongoing requirement for corticosteroid therapy for CNS disease
• Symptomatic peripheral neuropathy \> 2 grade NCIC-CTG criteria
• Serious, non-healing wound, ulcer, or bone fracture
• Evidence of bleeding diathesis or coagulopathy
• Uncontrolled hypertension and prior histor of hypertensive crisis or hypertensive encephalopathy

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead
• Roche Pharma AG: collaborator

Study Sites (1)

Francesca Vannini

Pisa, Italia, 56126, Italy

Location

Related Publications (3)

• Antoniotti C, Rossini D, Pietrantonio F, Salvatore L, Lonardi S, Tamberi S, Marmorino F, Moretto R, Prisciandaro M, Tamburini E, Tortora G, Passardi A, Bergamo F, Raimondi A, Ritorto G, Borelli B, Conca V, Ugolini C, Aprile G, Antonuzzo L, Gelsomino F, Martinelli E, Pella N, Masi G, Boni L, Galon J, Cremolini C. Upfront Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Bevacizumab With or Without Atezolizumab for Patients With Metastatic Colorectal Cancer: Updated and Overall Survival Results of the ATEZOTRIBE Study. J Clin Oncol. 2024 Aug 1;42(22):2637-2644. doi: 10.1200/JCO.23.02728. Epub 2024 Jun 12.

  PMID: 38865678 DERIVED

• Antoniotti C, Rossini D, Pietrantonio F, Catteau A, Salvatore L, Lonardi S, Boquet I, Tamberi S, Marmorino F, Moretto R, Ambrosini M, Tamburini E, Tortora G, Passardi A, Bergamo F, Kassambara A, Sbarrato T, Morano F, Ritorto G, Borelli B, Boccaccino A, Conca V, Giordano M, Ugolini C, Fieschi J, Papadopulos A, Massoue C, Aprile G, Antonuzzo L, Gelsomino F, Martinelli E, Pella N, Masi G, Fontanini G, Boni L, Galon J, Cremolini C; GONO Foundation Investigators. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2022 Jul;23(7):876-887. doi: 10.1016/S1470-2045(22)00274-1. Epub 2022 May 27.

  PMID: 35636444 DERIVED

• Antoniotti C, Borelli B, Rossini D, Pietrantonio F, Morano F, Salvatore L, Lonardi S, Marmorino F, Tamberi S, Corallo S, Tortora G, Bergamo F, Brunella DS, Boccaccino A, Grassi E, Racca P, Tamburini E, Aprile G, Moretto R, Boni L, Falcone A, Cremolini C. AtezoTRIBE: a randomised phase II study of FOLFOXIRI plus bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer. BMC Cancer. 2020 Jul 22;20(1):683. doi: 10.1186/s12885-020-07169-6.

  PMID: 32698790 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab; Irinotecan; Oxaliplatin; Leucovorin; Fluorouracil; atezolizumab

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 Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: prospective, open-label, multicentric phase II randomized in a 1:2 ratio

Study Record Dates

• First Submitted: October 25, 2018
• First Posted: October 26, 2018
• Study Start: November 30, 2018
• Primary Completion: June 15, 2021
• Study Completion: August 31, 2023
• Last Updated: October 12, 2023

Record last verified: 2023-10

Locations

IT (1)