A Study of Anti-PD-1 Combinations of D-CIK Immunotherapy and Axitinib in Advanced Ranal Carcinoma

Study Overview
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Brief Summary
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Phase II clinical trial to investigate the safety, clinical activity and toxicity of combinations of D-CIK and low dose anti-PD-1 antibody in patients with metastatic renal cell carcinoma treated with axitinib.

Detailed Description
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This is a phase II, single arm study to investigate the safety and efficacy of pembrolizumab-activated autologous D-CIK cells (CIK:Cytokine-induced killer, D-CIK:CIK cells are stimulated using mature dendritic cells) with Axitinib in patients with advanced kidney cancer. Heparinized peripheral blood was obtained from participants over a 1-week period. PBMCs(Peripheral blood mononuclear cells) were separated by Ficoll-Hypaque gradient centrifugation, suspended in X-VIVO 15 serum-free medium, and culture with 1000 U/ml rhIFN-γfor the first 24 h, followed by stimulation with 100 ng/ml OKT-3 , 1000 U/ml rhIL-2 and 100 U/ml IL-1α to activate the CIK.Dendritic cells were incubated with CIK. Fresh medium containing 1000 U/ml rhIL-2 was added every 2 days and the cell density was maintained at 2×10^6 cells/mL.D-CIK were harvested, washed, and resuspended after culture for 14 days. Before cell transfer,D-CIK were incubated with anti-PD-1 antibody(Pembrolizumab (Merck & Co., Inc.) is a humanized IgG4 anti-PD-1 monoclonal antibody that binds to PD-1 to prevent it from engaging with PD-L1 or PD-L2.), and a fraction of the D-CIK were collected to assess their number, phenotype, and viability of cells, and to test for possible contamination by bacteria, fungi, or endotoxins. Then, autologous D-CIK (1.0-1.5*10^10 cells) were transferred to patients via intravenous infusion. The present study was designed with Simon's best two stage study to explore the efficacy and safety of low-dose pembrolizumab in the treatment of patients with advanced renal cancer by D-CIK re-transfusion combined with Axitinib in vitro. The expected effective rate of the combined treatment is set at 60%, and if the effective rate is less than 30%, the effective rate of the combined treatment is considered to be at an undesirable level. The best two-stage design is 3/8, 10/24. In the first stage, 8 patients need to be treated. If the number of effective cases is less than 3, the combined treatment is deemed ineffective and the trial needs to be terminated. If the number of effective cases is more than 3, the phase II trial will be continued, and a total of 24 subjects need to be included.

Official Title
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A Study of Anti-PD-1( Pembrolizumab) Combinations of D-CIK (Cytokine-induced Killer Cells Are Stimulated Using Mature Dendritic Cells) Immunotherapy and Axitinib in Advanced Ranal Carcinoma

Conditions
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Renal Cancer Metastatic

Intervention / Treatment
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* Biological: Combinations treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: advanced renal clear cell carcinoma confirmed by pathology: high-volume disease without systemic treatment(including primary lesion unable to surgery, multiple lymph node metastases or distant metastases), or achieved disease progression after treatment by the anti-angiogenesis therapy (TKI or mTOR inhibitors) or by cytokines or combination therapy Predicted survival >=3 months At least 1 measurable lesion High-volume disease（meet one of the following criteria）:1. More than 3 sites of lesions with or without primary lesions, and at least 1 lesion routine CT or spiral CT scan >=3cm; 2. Unresected primary lesions (> 10cm), accompanied by 2 metastatic lesions; 3. After nephrectomy, single metastasis, at least 3 metastases, and at least one lesion > 2cm; 4. After nephrectomy, multiple metastatic(>3 organs) and at least one lesion > 2cm. Exclusion Criteria: Prior treatment with anti-PD-1/PD-L1/PD-L2 antibody and Axitinib Hypersensitivity to recombinant humanized anti-PD-1 monoclonal Abm or its components Severe cardiovascular and cerebrovascular diseases, uncontrollable severe hypertension and diabetes, severe renal insufficiency or uremia Long-term use of immunosuppressive agents after organ transplantation Immunosuppressive drugs are currently in use People with a clear and serious infection Predicted survival<3 months Patients with T cell lymphoma, myeloma Patients with autoimmune diseases HIV positive, or other immunodeficiency diseases Pregnant or nursing
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Autologous D-CIK (1.0-1.5*10^10 cells) will be transferred to patients via intravenous infusion. Before cell transfer, D-CIK were incubated with anti-PD-1 antibody.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combinations treatment<br>Drug: Axitinib 5mg orally twice a day Combination Treatment：Anti-PD-1 Combinations of D-CIK Immunotherapy | Biological: Combinations treatment<br>* Autologous dendritic and cytokine-induced killer cells (D-CIK)(1.0-1.5*10^10 cells)were incubated with low dose anti-PD-1 antibody（pembrolizumab, Merck & Co., Inc.） and were transferred to participants via intravenous infusion .<br>* Other names: pembrolizumab(Merck & Co., Inc.);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate（ORR）by irRC and RECIST 1.1 | The treatment effect of Anti-PD-1 combinations of D-CIK immunotherapy and axitinib,will be assessed using irRC and RECIST 1.1 to determine tumor response. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival（PFS）by irRC and RECIST 1.1 | The treatment effect of Anti-PD-1 combinations of D-CIK immunotherapy and axitinib, will be assessed using irRC and RECIST 1.1 to determine progression-free survival time. | 3 years | 
| Overall Survival (OS) by irRC and RECIST 1.1 | The treatment effect of Anti-PD-1 combinations of D-CIK immunotherapy and axitinib, will be assessed using irRC and RECIST 1.1 to determine overall survival time. | 3 years | 
| Duration of Response (DOR) by irRC and RECIST 1.1 | The treatment effect of Anti-PD-1 combinations of D-CIK immunotherapy and axitinib, will be assessed using irRC and RECIST 1.1 to determine duration of response. | 3 years | 
| The quality of life by EQ-5D-5L and NCCN-FACT FKSI-19 v2.0. | The treatment effect of Anti-PD-1 combinations of D-CIK immunotherapy and axitinib, will be assessed using EQ-5D-5L and NCCN-FACT FKSI-19 v2.0.to determine the quality of life. | 3 years | 
| Severity of adverse events as assessed by CTCAE v4.0 |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ranal Carcinoma, Immunotherapy, Axitinib