Efficacy and Safety of Chemotherapy Plus Bevacizumab and Anti-PD-1 Followed by Induction Therapy of Chemotherapy Plus Bevacizumab as First-line Therapy in MSS Unresectable Metastatic Colorectal Cancer: a Prospective, Single-center, Single-arm Trial
Overview
- Phase
- Phase 2
- Intervention
- mFOLFOX6 regimen + bevacizumab + PD-1 monoclonal antibody
- Conditions
- Metastatic Colorectal Cancer
- Sponsor
- Zhangfa Song
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- progression free survival(PFS)
- Status
- Not yet recruiting
- Last Updated
- last year
Overview
Brief Summary
Fluorouracil and oxaliplatin-based combined with molecular targeted drugs are still the main treatment strategies for patients with advanced metastatic colorectal cancer (mCRC). Multiple studies have confirmed that anti-PD-1 combined chemotherapy regimens can bring better survival benefits to patients with advanced mCRC. Slulimab is a humanized IgG4 monoclonal antibody with clear anti-tumor efficacy and easy management of adverse reactions. Therefore, the main purpose of this study is to explore the effectiveness of chemotherapy and bevacizumab induction therapy combined with PD-1 monoclonal antibody in the first-line treatment of MSS-type initial unresectable mCRC.
Detailed Description
Colorectal Cancer (CRC) is a common malignant tumor. Its incidence ranks third and second among men and women respectively, and its mortality rate ranks third. Data from the World Health Organization's International Agency for Research on Cancer (IARC) in 2020 show that more than 930,000 patients died due to CRC. Since 2000, the incidence and mortality of colorectal cancer have been steadily increasing in China. The National Cancer Center of China (NCC) reported that there were approximately 408,000 new cases of CRC in China in 2016, and approximately 196,000 deaths. Most of the patients are in the mid-to-late stage when diagnosed, and about 35% of them are in the advanced stage. They have no chance of radical surgery and can only receive palliative care. In the early days when leucovorin (LV) and 5-fluorouracil (5-FU) were used as the main treatment options for patients with metastatic colorectal cancer (mCRC), the efficacy was poor, and the median overall survival (OS) of patients was only for 8-12 months. Since the introduction of effective cytotoxic drugs such as irinotecan and oxaliplatin in 2000, the combination regimens FOLFOX (5-FU/LV + oxaliplatin) and FOLFIRI (5-FU/LV + irinotecan) have become first-line systemic Standard protocol in treatment. The use of biologics targeting key pathways in the development and progression of mCRC, such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)-related pathways, further extends the survival of mCRC patients. In the latest version of CSCO colorectal cancer diagnosis and treatment guidelines, the main recommended first-line treatments are FOLFOX/FOLFIRI±bevacizumab or cetuximab (both RAS and BRAF are wild-type), FOLFOX/FOLFIRI±bevacizumab (RAS or BRAF mutant). PD-1 plays an important role in suppressing immune responses and promoting immune tolerance by inhibiting the activity of T cells, allowing cancer cells to evade immune surveillance. Cells in the tumor microenvironment often express PD-1 and PD-L1. Consistent with the inducible expression of PD-L1 by tumor cells, activated CD8+ effector T cells often express PD-1, indicating that tumor cells are resistant to adaptive immune responses. PD-L1 has been found to be expressed in many types of cancer, including melanoma, lung cancer, urothelial cancer, and hepatocellular carcinoma. Its expression can also be induced by various factors such as radiation, which helps cancer cells evade immune regulation. Blocking the PD-1/PD-L1 interaction has been shown to treat a variety of cancers. Clinical studies have proven that anti-PD-1 and anti-PD-L1 monoclonal antibodies can induce long-lasting anti-tumor activity against a variety of tumors. Anti-PD-1 monoclonal antibodies have been approved for the treatment of melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, entities with high microsatellite instability or mismatch repair deficiency and colorectal cancer, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), renal cell carcinoma, endometrial cancer, bladder cancer, primary mediastinal large B-cell lymphoma ( PMBCL) and classic Hodgkin lymphoma. A large number of clinical studies of anti-PD-1 antibodies are currently underway, some as monotherapy and some in combination with multiple drugs. This study is an open-label, single-arm, phase II clinical trial. The study inclusion criteria are patients with unresectable mCRC aged 18-75 years old and histologically confirmed by multidisciplinary treatment (MDT). The patients have RAS gene mutations and are confirmed to be MSS. state. All patients received treatment with sintilimab combined with CapeOx and bevacizumab. After the disease achieved complete response (CR)/partial response (PR)/stable disease (SD), maintenance treatment was performed. The main purpose of the study Endpoints include objective response rate (ORR) as assessed by RECIST v1.1 and adverse events as assessed by CTCAE v5.0. The secondary endpoint is progression-free survival (PFS). This study mainly aims to explore the effectiveness of chemotherapy and bevacizumab induction therapy combined with PD-1 monoclonal antibody in the first-line treatment of MSS-type initial unresectable metastatic colorectal cancer. The second is its safety and tolerability.
Investigators
Zhangfa Song
Professor
Sir Run Run Shaw Hospital
Eligibility Criteria
Inclusion Criteria
- •The patient volunteered to participate in the study, signed the informed consent form, and had good compliance.
- •Age: 18-75 years old (including 18 years old and 75 years old).
- •Body weight of 40kg.
- •Metastatic colorectal cancer confirmed by histology and / or cytology and initially unresectable.
- •MSS type or pMMR.
- •Patients are required to have at least one measurable lesion (RECIST 1.1).
- •ECOG physical strength status: 0-1 point.
- •Expected survival of 12 weeks.
- •Blood test (no transfusion within 14 days, no correction with granulocyte colony stimulating factor or other hematopoietic stimulating factor within 7 days before the laboratory test)
- •Absolute neutrophil value of 1.5109/ L, platelet 1010109/ L, hemoglobin concentration of 9 g/dL);
Exclusion Criteria
- •Have received the following treatments within the first 4 weeks of treatment: tumor radiotherapy, surgery, chemotherapy, immune or molecular targeted therapy, and other clinical study drugs.
- •Active autoimmune diseases requiring systemic treatment (i. e., corticosteroids or immunosuppressive agents) have occurred in the past 2 years. Alternative therapies (such as thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) are not considered systemic treatment.
- •Diagnosis with immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first treatment. A physiological dose of corticosteroids may be approved after consultation with the investigator.
- •Previous small molecule targeted drug therapy, such as fuquintinib, etc.
- •Previous treatment with an oxaliplatin-based chemotherapy regimen.
- •Symptomatic brain or meningeal metastases.
- •Metastatic colorectal cancer with either MSI-H or dMMR.
- •Severe infection (e. g. intravenous infusion of antibiotics, antifungals or antiviral drugs), or unexplained fever\> 38.5℃ during screening / first dose.
- •Hypertension that is not well controlled with antihypertensive medication (systolic 140 mmHg or diastolic 90 mmHg).
- •Significant clinical bleeding symptoms or significant bleeding tendency (bleeding\> 30 mL, hematemesis, black feces, stool within 3 months), hemoptysis (\> 5 mL of fresh blood within 4 weeks); or venous / venous thrombosis events within 6 months, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism; or long-term anticoagulation with Chinese standard or heparin, or long-term antiplatelet therapy (aspirin 300 mg / day or clopidogrel 75 mg / day).
Arms & Interventions
mFOLFOX6 regimen + bevacizumab + PD-1 monoclonal antibody
Induction therapy: mFOLFOX6 regimen + bevacizumab. mFOLFOX6 regimen: Oxaliplatin 85 mg/m2 ; LV 400 mg/m2; 5-FU 400 mg/m2, Intravenous bolus injection, day 1, then maintain 1200mg/(m2∙d) × 2d continuous intravenous infusion (total volume 2400mg/m2, infusion 46-48h), q2w; Bevacizumab: 5mg/kg; lasting 2 cycles. Combination therapy: mFOLFOX6 regimen + bevacizumab + PD-1 monoclonal antibody. mFOLFOX6 regimen: Oxaliplatin 85 mg/m2 intravenously infused for 90-120 minutes on day 1; LV 400 mg/m2 intravenous infusion for 2 hours, combined with oxaliplatin injection time on day 1; 5-FU 400 mg/m2, Intravenous bolus injection, day 1, then maintain 1200mg/(m2∙d) × 2d continuous intravenous infusion (total volume 2400mg/m2, infusion 46-48h), q2w; bevacizumab: 5mg/kg, intravenously Infusion, day 1, q2w; Slulimab: 200 mg, intravenous infusion, day 1, q2w. Every 2 weeks is a cycle.
Intervention: mFOLFOX6 regimen + bevacizumab + PD-1 monoclonal antibody
Outcomes
Primary Outcomes
progression free survival(PFS)
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
The time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first.
Secondary Outcomes
- overall survival(OS)(5 years)
- objective response rate(ORR)(through study completion, an average of 1 year)
- disease control rate(DCR)(through study completion, an average of 1 year)
- Adverse events(through study completion, an average of 1 year)