Low-dose Immunotherapy in Metastatic and Locally Advanced Colorectal and Gastric MSI/dMMR Cancers

Phase II Open-lable Single-center Clinical Study of the Efficacy and Safety of Low-dose Immunotherapy in the Treatment of Patients With Metastatic and Locally Advanced Colorectal and Gastric Cancers With Microsatellite Unstable Phenotype (MSI)/Deficiency of Mismatch Repair System (dMMR)

It is planned to study the effectiveness of low-dose immunotherapy (IT) nivolumab 40 mg for either 2 courses of therapy or 6 courses as preoperative therapy in patients with dMMR/MSI locally advanced CRC. Parallel recruitment into subgroups of patients by randomization is assumed.

For dMMR/MSI locally advanced gastric cancer, it is planned to study the effectiveness of low-dose immunotherapy nivolumab 40 mg with or without the addition of chemotherapy (CT) in the FOLFOX regimen as preoperative therapy.

Subgroup A includes 6 cycles of IV CT FOLFOX + IV administration of nivolumab 40 mg once every 14 days, subgroup B - 2 cycles of intravenous administration of nivolumab at a dose of 40 mg once every 14 days, and subgroup C - 6 cycles of intravenous administration of nivolumab at a dose of 40 mg once a day 14 days. Thus, it is planned to gradually include patients in the treatment subgroups.

The frequency of complete therapeutic tumor pathomorphoses (pCR, TRG1) will be evaluated as the primary endpoint. Secondary goals are to study the safety of drug doses, to assess the frequency of pronounced therapeutic tumor pathomorphoses (MPR, TRG 1-2), to assess disease-free survival (PFS), the frequency of R0 resections, overall survival(S), and the frequency of objective response.

To study the use of low-dose immunotherapy in combination with chemotherapy in patients with metastatic dMMR/MSI CRC and gastric cancer in the first line of therapy, it is planned to use a combination of nivolumab 40 mg with FOLFOX regimen once every 14 days for 8 treatment cycles, followed by a switch to supportive intravenous monotherapy with nivolumab 40 mg.

It is planned to study the effectiveness of low-dose immunotherapy (IT) nivolumab 40 mg for either 2 courses of therapy or 6 courses as preoperative therapy in patients with dMMR/MSI locally advanced CRC. Parallel recruitment into subgroups of patients by randomization is assumed.

For dMMR/MSI locally advanced gastric cancer, it is planned to study the effectiveness of low-dose immunotherapy nivolumab 40 mg with or without the addition of chemotherapy (CT) in the FOLFOX regimen as preoperative therapy.

Subgroup A includes 6 cycles of IV CT FOLFOX + IV administration of nivolumab 40 mg once every 14 days, subgroup B - 2 cycles of intravenous administration of nivolumab at a dose of 40 mg once every 14 days, and subgroup C - 6 cycles of intravenous administration of nivolumab at a dose of 40 mg once a day 14 days. Thus, it is planned to gradually include patients in the treatment subgroups.

The frequency of complete therapeutic tumor pathomorphoses (pCR, TRG1) will be evaluated as the primary endpoint. Secondary goals are to study the safety of drug doses, to assess the frequency of pronounced therapeutic tumor pathomorphoses (MPR, TRG 1-2), to assess disease-free survival (PFS), the frequency of R0 resections, overall survival(S), and the frequency of objective response.

To study the use of low-dose immunotherapy in combination with chemotherapy in patients with metastatic dMMR/MSI CRC and gastric cancer in the first line of therapy, it is planned to use a combination of nivolumab 40 mg with FOLFOX regimen once every 14 days for 8 treatment cycles, followed by a switch to supportive intravenous monotherapy with nivolumab 40 mg.

One-year AFD will be evaluated as the primary endpoint in the group with metastatic disease. Secondary goals are to study the safety of drug doses, and to evaluate one-year DFS, OS, and CSR.

To develop methods for personalizing low-dose IT, it is planned to compare the number of PD-1-positive cells before treatment and during immunotherapy. It is expected to detect PD-1 blockade on the lymphocyte surface during therapy and assess its duration. The results of the study will be presented in the form of an indicator of the number of PD-1-positive cells (%) and an indicator of the protein density on the surface of positive cells (MFI - average fluorescence intensity).

Peripheral venous blood samples in an anticoagulant tube (3 ml) are planned before the start of therapy, before the second injection of anti-PDL antibodies and, if long-term immunotherapy is received, after 8 weeks. Monoclonal antibodies to CD45, CD4, CD8, CD279 (PD-1), and IgG4 will be used as reagents. The equipment is a BD FACS Canto II flow cytometer.

To analyze the features of radiological evaluation of the effectiveness of checkpoint inhibitor therapy (pseudoprogression), radiological monitoring will be performed before the start of therapy, before surgical treatment, and every 8 weeks of treatment with prolonged immunotherapy. The response to treatment will be evaluated according to the RECIST criteria in revision 1.1.

Inclusion Criteria:

• Availability of voluntarily signed informed consent from the patient;
• Men and women, 18 years old </=;
• Histologically confirmed adenocarcinoma of the colon/rectum/stomach;
• Presence of MSI/dMMR in the tumor;
• For M0-cohort: locally advanced tumor - cT3-4N0-2M0 according to CT for tumors of the colon and sigmoid colon; cT3 with a depth of tissue invasion ≥5mm (cT2N0 and higher for lower ampullary cancer) or T4 or involvement of the lateral resection margins according to MRI for rectal cancer; for gastric cancer: cT2</=, N0-3, no presence of tumour cells in peritoneum (cyt-);
• For M1-cohort: non-resectable locally-advanced, metastatic disease
• ECOG 0-2;
• No contraindications to surgical treatment of malignancy

Exclusion Criteria:

• Previous therapy with the inclusion of monoclonal antibodies - anti-PD1, anti-PD-L1, anti PD-L2, anti-CTLA4 antibodies and other immunotherapy drugs
• The presence of any other malignant tumor, with the exception of radically treated basal cell carcinoma, cervical cancer in situ, currently or within 5 years before inclusion in the study
• Pregnant and lactating women, as well as planning pregnancy during the period of therapy in a clinical trial and 6 months after the end of therapy
• Patients with preserved reproductive potential who refuse to use adequate methods of contraception throughout the study and 6 months after the end of therapy or who agree to abstain from heterosexual contact.
• Previous systemic therapy with immunosuppressive drugs (including, but not limited to: prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide and TNF [tumor necrosis factor] antagonists) within 4 weeks before signing the informed consent form, or the need to use immunosuppressive therapy in during the first year of the study.
• The use of systemic glucocorticosteroids (GCS) in replacement doses (for example, in a dose equivalent to 10 mg of prednisolone per day or less), short-term use of systemic GCS (≤7 days), inhaled and topical GCS are allowed.
• Active, known or suspected autoimmune diseases (patients with type 1 diabetes mellitus and hypothyroidism requiring only hormone replacement therapy, as well as autoimmune diseases with only skin manifestations [for example, vitiligo, alopecia or psoriasis without symptoms of psoriatic arthritis] are allowed to participate), that do not require systemic therapy);
• Patients with HIV infection, active hepatitis B, active hepatitis C.
• Life expectancy less than 6 months.
• The presence of a disease or condition that, in the opinion of the investigator, prevents the patient from participating in the study.
• Complicated course of the primary tumor, requiring urgent surgical intervention.
• Previously performed radiation or chemotherapy for colorectal cancer or gastric cancer, with the exception of cases of metachronous tumors over 5 years ago;
• Persistence, progression or recurrence of the underlying disease or the presence of distant metastases
• Conditions limiting the patient's ability to comply with the requirements of the protocol (in the opinion of the investigator);
• Vaccination with live vaccines within 28 days before randomization;
• Participation in other interventional clinical trials less than 30 days before randomization (except in cases of dropout before the introduction of study therapy) and while participating in an ongoing clinical trial;
• Significant adverse events from previous therapy, with the exception of chronic and/or irreversible events that cannot influence the assessment of the safety of the study therapy (for example, alopecia);
• Hypersensitivity or allergic reactions to the administration of drugs manufactured using Chinese hamster ovary cells, severe allergic reactions, anaphylaxis or other hypersensitivity reactions to chimeric or humanized antibodies, or any of the components of the study drug.