Treatment of Colorectal Liver Metastases With Immunotherapy and Bevacizumab
- Conditions
- Colorectal NeoplasmsNeoplasm MetastasisColonic NeoplasmsRectal Neoplasms
- Interventions
- Registration Number
- NCT03698461
- Lead Sponsor
- Asan Medical Center
- Brief Summary
Liver is the most common site of metastases from colorectal cancer. Neoadjuvant chemotherapy with targeted agents is usually recommended for borderline-resectable liver metastases that are technically difficult to resect for conversion to resectable disease and control of metastatic spread. However, the prognosis of these patients are still poor, and long term disease-free survival over 3 years is rare and \<20%. More effective measures to prevent recurrence are needed before or after resection of colorectal liver metastases.
- Detailed Description
* Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets Programmed Death-Ligand 1(PD-L1) and inhibits the interaction between PD-L1 and its receptors, Programmed cell Death protein 1(PD-1) and B7.1. Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude and quality of tumor specific T cell responses, resulting in improved anti tumor activity.
* Bevacizumab is a recombinant, humanized therapeutic antibody directed against vascular endothelial growth factor(VEGF). In addition to its well-characterized role in angiogenesis, VEGF is also believed to be involved in cancer immune evasion via the induction of myeloid- derived suppressor cells(MDSCs). These VEGF-induced MDSCs can suppress both T-cell and dendritic-cell function. Bevacizumab can restore and/or maintain the antigen presentation capacity of dendritic cells, leading to enhanced T-cell infiltration in tumors. When used in combination, VEGF targeting agents such as bevacizumab promote the normalization of tumor vasculature and may thereby increase access of therapeutic agents.
* Atezolizumab with bevacizumab, levoleucovorin, oxaliplatin, and 5-fluorouracil(FOLFOX). A translational study for renal cell carcinoma showed bevacizumab resulted in modulation of tumor immune microenvironment with Th1-related signatures, which was more potentiated by subsequent treatment with atezolizumab. This suggests potentiation of anti-tumor immunity with the combination of bevacizumab and atezolizumab.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 20
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Atezolizumab, Bevacizumab, FOLFOX Atezolizumab Atezolizumab 1200mg IV Once, Atezolizumab (840mg IV D1 of C1-12) + Bevacizumab (5mg/kg IV D1 of C1-12) + FOLFOX(Oxaliplatin 85mg/m2 IV D1 of C1-12, Levoleucovorin 200mg/m2 IV D1 of C1-12, 5-FU - bolus 400mg/m2 IV D1 of C1-12, - infusional 2400mg/m2 IV continuous(46 hours) D1-3 of C1-12) Atezolizumab, Bevacizumab, FOLFOX Bevacizumab Atezolizumab 1200mg IV Once, Atezolizumab (840mg IV D1 of C1-12) + Bevacizumab (5mg/kg IV D1 of C1-12) + FOLFOX(Oxaliplatin 85mg/m2 IV D1 of C1-12, Levoleucovorin 200mg/m2 IV D1 of C1-12, 5-FU - bolus 400mg/m2 IV D1 of C1-12, - infusional 2400mg/m2 IV continuous(46 hours) D1-3 of C1-12) Atezolizumab, Bevacizumab, FOLFOX Oxaliplatin Atezolizumab 1200mg IV Once, Atezolizumab (840mg IV D1 of C1-12) + Bevacizumab (5mg/kg IV D1 of C1-12) + FOLFOX(Oxaliplatin 85mg/m2 IV D1 of C1-12, Levoleucovorin 200mg/m2 IV D1 of C1-12, 5-FU - bolus 400mg/m2 IV D1 of C1-12, - infusional 2400mg/m2 IV continuous(46 hours) D1-3 of C1-12) Atezolizumab, Bevacizumab, FOLFOX Levoleucovorin Atezolizumab 1200mg IV Once, Atezolizumab (840mg IV D1 of C1-12) + Bevacizumab (5mg/kg IV D1 of C1-12) + FOLFOX(Oxaliplatin 85mg/m2 IV D1 of C1-12, Levoleucovorin 200mg/m2 IV D1 of C1-12, 5-FU - bolus 400mg/m2 IV D1 of C1-12, - infusional 2400mg/m2 IV continuous(46 hours) D1-3 of C1-12) Atezolizumab, Bevacizumab, FOLFOX 5-FU Atezolizumab 1200mg IV Once, Atezolizumab (840mg IV D1 of C1-12) + Bevacizumab (5mg/kg IV D1 of C1-12) + FOLFOX(Oxaliplatin 85mg/m2 IV D1 of C1-12, Levoleucovorin 200mg/m2 IV D1 of C1-12, 5-FU - bolus 400mg/m2 IV D1 of C1-12, - infusional 2400mg/m2 IV continuous(46 hours) D1-3 of C1-12)
- Primary Outcome Measures
Name Time Method Serial changes in Cluster of Differentiation(CD) 8+ T cell densities Baseline, Day15 of first atezolizumab administration, and after at least 6 cycles (each cycle is 14days) Opal(TM) platform Immunohistochemistry(IHC)
- Secondary Outcome Measures
Name Time Method Serial changes of Density of Vascular marker CD31, CD34 Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days) Opal(TM) platform IHC
Serial changes of Gene expression profile Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days) RNA-seq
Response Rate Baseline, at 6th week from the first treatment, and then every 6±2 weeks up to 12 cycles (each cycle is 14days), every 3 months after the 12 cycles up to 24months RECIST 1.1 and immune RECIST(iRECIST)
Serial changes of Immune cell biomarkers CD3, CD4, Programmed death-Ligand 1(PD-L1),PD-1, granzyme B, CD45RO, Forkhead Box P3(FOXP3), CD68 Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days) Opal(TM) platform IHC
Serial changes of Immune cell CD3+, CD8+ densities Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days) IMMUNOSCORE® (IMMUNOSCORE is a registered trademark owned by INSERM)
Incidence, nature and severity of adverse events with severity (Safety profile) Consent to 90 days after the last dose of investigational medicinal product or until initiation of new systemic anti-cancer therapy, whichever occurs first. Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Microbiome profile Day1 before first atezolizumab administration, Day15 before the treatment and at time of hepatic metastasectomy or liver biopsy after 6 cycles of treatment (each cycle is 14days) In stool samples through whole metagenomic sequencing
R0 resection rate At the time of hepatic resection All gross lesions are resected and all surgical margins are free from tumor cells (The proportion of patients who undergo R0 resection for liver metastases out of all patients who started at least one dose of study treatment.)
Progression-Free Survival Baseline, at 6th week from the first treatment, and then every 6±2 weeks up to 12 cycles (each cycle is 14days), every 3 months after the 12 cycles up to 24months RECIST 1.1 and iRECIST
Trial Locations
- Locations (1)
Asan Medical Center
🇰🇷Seoul, Songpa-gu, Korea, Republic of