Development of a New Immunotherapy Using Intramuscular Administration of Autologous Total IgG

Study Overview
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Brief Summary
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The purpose of this prospective pilot clinical study is to evaluate the safety and immunostimulatory effect of intramuscularly administrations of autologous total IgG (autologous total IgG therapy) in healthy subjects and patients with advanced solid tumor (non-small cell lung cancer, stomach cancer, colon cancer, ovarian cancer, breast cancer, pancreatic cancer, biliary cancer, melanoma, renal cell carcinoma etc.). In addition, antitumor effect of intramuscularly administrations of autologous total IgG in patients with advanced solid tumor will be also evaluated.

Detailed Description
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After providing informed consent, study participants will be assessed for study eligibility at the screening visit. At screening visit (week -4), venous blood (320 400 mL) will be sampled using a double blood bag containing anticoagulant. Autologous plasma will be separated from the venous blood by centrifugation. During the 4 weeks of screening period, autologous total IgG (purity ≥97%) will be aseptically purified from the autologous plasma by chromatography using Protein A. Participants will receive the 8 intramuscular injections of autologous total IgG, twice a week for 4 weeks from baseline (week 0). The investigators will evaluate the safety and immunostimulatory effect of intervention of this study by analyzing side effects, serum concentrations of immunological parameters (immunoglobulin, cytokine, etc.), and lymphocyte fraction by flow cytometry analysis of peripheral blood mononuclear cells. [Part A) Autologous total IgG therapy in healthy subjects] The duration of this clinical study in healthy subjects is 16 weeks from the screening visit. A 4-week screening period will be followed by a 4-week intervention period and an 8-week follow-up period. [Part B) Autologous total IgG therapy in patients with advanced solid tumor] The duration of this clinical study in patients with advanced solid tumor is 12 weeks from the screening visit. A 4-week screening period will be followed by a 4-week intervention period and a 4-week follow-up period(1 cycle). If the patients agree to participate in additional long-term repeated study interventions at the end of 1st cycle of visit, patients will receive repeated study interventions in same the schedule up to week 44 (maximum 4 cycles). At the end of each cycle, antitumor effect will be evaluated by serum tumor marker concentrations, anatomical imaging, and Response Evaluation Criteria in solid tumors (RECIST ver. 1.1).

Official Title
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Evaluation of Immunostimulatory Effect of Intramuscular Administration of Autologous Total IgG in Human for Development of a New Immunotherapy

Conditions
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Immunotherapy

Intervention / Treatment
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* Biological: Part A) Healthy subjects
* Biological: Part B) Advanced solid tumor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 19 years or older Meeting the criteria for autologous blood donation 1) Body weight ≥32 kg (satisfying body weight limitation for planned sampling of 320 mL of venous blood volume) 2) Hemoglobin: ≥ 9 g/dL (Healthy volunteers Hemoglobin: ≥ 11 g/dL) Provide signed informed consent [Only for patients with advanced solid tumor] Patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2 at the time of study enrollment. [Only for patients with advanced solid tumor] Patients with a life expectancy longer than 3 months and metastatic (stage Ⅲ, Ⅳ) advanced solid tumor (non-small cell lung cancer, stomach cancer, colon cancer, ovarian cancer, breast cancer, pancreatic cancer, cholangiocarcinoma, malignant melanoma, renal cell carcinoma, etc.) [Only for patients with advanced solid tumor] One or more target lesions must be present as confirmed by anatomical imaging (X-ray, CT sacn, MRI, etc.) Exclusion Criteria: Subjects under the age of 19 year, or unable to agree on their own (emergency patients, patients with mental disability, patients with limited capacity to consent due to stroke or delirium caused by diabetes), or severe disease whose expected survival duration is less than 3 months Pregnancy or planned pregnancy within 1 year Subjects who participated on another investigational device or drug studies within 4 weeks prior to screening visit Medical history of alcohol or drug abuse within 2 years of the screening visit Subjects is a member of the investigational team Unable to comply with all clinic visits and study-related procedures Planned or anticipated major surgical procedure within 4 weeks prior to baseline visit [Only for patients with advanced solid tumor] A well-treated patients in combination with surgery and radiotherapy [Only for patients with advanced solid tumor] Uncontrolled infections (bacterial, viral, fungal infection) [Only for patients with advanced solid tumor] Has known active brain metastases(except for subjects with adequate treated and neurological asymptomatic at least 2 weeks, subjects without neurological symptoms without treatment for brain metastases, also subjects must be either off corticosteroid for corticosteroid therapy, or who have received stable doses of prednisone less than 10mg daily or who have received reduced doses may be enrolled.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Intramuscularly administrations of autologous total IgG in healthy subjects and patients with advanced solid tumor
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A) Healthy subjects<br>Part A) Autologous total IgG 50mg will be administered to the healthy subjects by intramuscular injections, twice a week for 4 weeks (total 8 injections). | Biological: Part A) Healthy subjects<br>* Part A) Autologous total IgG 50mg will be administered to the healthy subjects by intramuscular injections, twice a week for 4 weeks (total 8 injections).<br>* Other names: Intramuscular injections of autologous total IgG;|
| Experimental: Part B) Advanced solid tumor<br>Part B) Autologous total IgG 50mg will be administered to the patients with advanced solid tumor by intramuscular injection, twice a week for 4 weeks (total 8 injections). | Biological: Part B) Advanced solid tumor<br>* Part B) Autologous total IgG 50mg will be administered to the patients with advanced solid tumor by intramuscular injection, twice a week for 4 weeks (total 8 injections).<br>* Other names: Intramuscular injections of autologous total IgG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with severe adverse events (AEs), serious adverse events (SAEs), treatment-related AEs, deaths, or discontinuation of study intervention due to AEs in healthy subjects |  | From baseline to week 12 | 
| Number of participants with severe adverse events (AEs), serious adverse events (SAEs), treatment-related AEs, deaths, or discontinuation of study intervention due to AEs in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with abnormal serum chemistry results and blood test results due to clinical study in healthy subjects |  | From baseline to week 12 | 
| Serum concentrations of immunological parameters (immunoglobulin, cytokine, etc.) in healthy subjects |  | From baseline to week 12 | 
| Lymphocyte fraction by flow cytometry analysis of peripheral blood mononuclear cells in healthy subjects |  | From baseline to week 12 | 
| Levels of cytokines secreted from peripheral blood cells in healthy subjects |  | From baseline to week 12 | 
| Quality of life (5-level EuroQoL Group's 5-dimension; EQ-5D-5L) in healthy subjects | The 5-level EuroQoL Group's 5-dimension (EQ-5D-5L) consists of 2 parts: the descriptive system and the EQ visual analogue scale (VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels of perceived problems: no problems, slight problems, moderate problems, severe problems, and unable to/extreme problems. In addition, the EQ-5D-5L include an EQ-VAS where the endpoints are labeled on a scale from 0 (worst imaginable health) to 100 (best imaginable health). | From baseline to week 12 | 
| Subjective index of pain and fatigue (Visual Analogue Scale; VAS, Numeral Rating Scale; NRS) in healthy subjects | The 100-mm Visual Analogue Scale (VAS) ranges from 0 (absent) to 10 (worst imaginable). The 11-point Numerical Rating Scale (NRS) ranges from 0 (absent) to 10 (worst imaginable). | From baseline to week 12 | 
| Number of participants with abnormal serum chemistry results and blood test results due to clinical study in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Serum concentrations of immunological parameters (immunoglobulin, cytokine, etc.) in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Lymphocyte fraction by flow cytometry analysis of peripheral blood mononuclear cells in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Levels of cytokines secreted from peripheral blood cells in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Objective response rate (ORR) in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Disease control rate (DCR) in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Duration of response (DOR) in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Progression-free survival (PFS) in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Overall survival (OS) in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| The tumor marker concentrations in patients with advanced solid tumor |  | From baseline to week 8 and through study completion, an average of 3 year | 
| Quality of life (5-level EuroQoL Group's 5-dimension; EQ-5D-5L) in patients with advanced solid tumor | The 5-level EuroQoL Group's 5-dimension (EQ-5D-5L) consists of 2 parts: the descriptive system and the EQ visual analogue scale (VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels of perceived problems: no problems, slight problems, moderate problems, severe problems, and unable to/extreme problems. In addition, the EQ-5D-5L include an EQ-VAS where the endpoints are labeled on a scale from 0 (worst imaginable health) to 100 (best imaginable health). | From baseline to week 8 and through study completion, an average of 3 year | 
| Subjective index of pain and fatigue (Visual Analogue Scale; VAS, Numeral Rating Scale; NRS) in patients with advanced solid tumor | The 100-mm Visual Analogue Scale (VAS) ranges from 0 (absent) to 10 (worst imaginable). The 11-point Numerical Rating Scale (NRS) ranges from 0 (absent) to 10 (worst imaginable). | From baseline to week 8 and through study completion, an average of 3 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunoglobulin G, Treatment, Immunostimulatory effect, Tumor, Solid tumor