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A Study of Combinations of D-CIK Immunotherapy And Anti-PD-1 In Refractory Solid Tumors

Primary Purpose

Hepatocellular Carcinoma, Renal Cell Carcinoma, Bladder Cancer

Status

Unknown status

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

D-CIK and anti-PD-1 antibody

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring Refractory solid tumors, Dendritic and Cytokine-induced killer cell, Anti-PD-1 antibody, Combination immunotherapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participantswith treatment-refractory advanced hepatocellular carcinoma, renal cell carcinoma,bladder cancer,colorectal cancer,non-small-cell lung cancer,breast cancer and other solid cancers.
Age 18 to 75 years.
Willing to sign a durable power of attorney.
Able to understand and sign the Informed Consent Document.
Life expectancy of greater than three months.
An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the preparative regimen.
Adequate organ function.
Serology:
- Seronegative for HIV antibody.
- Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
Hematology:
- WBC (> 3000/mm(3)).
- Platelet count greater than 100,000/mm(3).
- Hemoglobin greater than 8.0 g/dl.
Chemistry:
- Serum ALT/AST less or equal to 2.5 times the upper limit of normal.
- Serum creatinine less than or equal to 1.6 mg/dl.
- Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

Exclusion Criteria:

Previous treatment with anti-CTLA-4 and anti-PD-1/PD-L1.
Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
History of autoimmune disease
Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
Concurrent antineoplastic therapies and systemic steroid therapy.

Sites / Locations

Sun Yat-Sen University, Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

D-CIK and anti-PD-1 Immunotherapy

Arm Description

D-CIK was incubated with anti-PD-1 antibody before infused back into participants

Outcomes

Primary Outcome Measures

Progress-free survival(PFS)

PFS is defined as the time from the combined therapy until objective tumor progression or death.

Secondary Outcome Measures

Overall survival (OS)

OS is defined as the time from the combined therapy until death from any cause

Laboratory findings

The number and secreted cytokines of CD3+ (or CD8+ or CD4+ or CD56+) T cells

Objective response rate

The total number of Complete remission and Partial remission (According to the response criteria in solid tumor(RECIST))

Severity of adverse events

According to National Cancer Institute Common Terminology Criteria for Adverse Events（NCI-CTCAE)

Full Information

NCT ID

NCT02886897

First Posted

August 14, 2016

Last Updated

August 26, 2016

Sponsor

Sun Yat-sen University

1. Study Identification

Unique Protocol Identification Number

NCT02886897

Brief Title

A Study of Combinations of D-CIK Immunotherapy And Anti-PD-1 In Refractory Solid Tumors

Official Title

A Phase II Study of Combinations of Dendritic Cells and Cytokine-induced Killer Cell （D-CIK) Immunotherapy And Anti-Programmed Death-1 In Refractory Solid Tumors

Study Type

Interventional

2. Study Status

Record Verification Date

August 2016

Overall Recruitment Status

Unknown status

Study Start Date

July 2016 (undefined)

Primary Completion Date

September 2019 (Anticipated)

Study Completion Date

October 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Sun Yat-sen University

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Background: Combinations of dendritic and cytokine-induced killer cell (D-CIK) based adoptive immunotherapy and anti-PD-1 antibody may enhance the immune response and stop cancer cells from growing. Objective: Phase II clinical trial to investigate the safety, clinical activity and toxicity of combinations of D-CIK and anti-PD-1 antibody in patients with treatment-refractory solid tumors. Methodology: Phase II clinical trial in patients with advanced metastatic hepatocellular carcinoma, renal cell carcinoma,bladder cancer,colorectal cancer,non-small-cell lung cancer,breast cancer and other solid cancers. The D-CIK was isolated from peripheral blood of participants,then activated,expanded and incubated with anti-PD-1 antibody before infusion. The enough number (1.0-1.5 *10^10 cells) of D-CIK were infused back into participants.

Detailed Description

Heparinized peripheral blood was obtained from participants over a 2-week period. PBMCs 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 OKT3 , 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,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. Generally, participants received at least 4 cycles of treatment at 2-week intervals or received doses until disease progression occurred. If the participants were disease-stable, additional cycles of maintenance treatment were eligible. Participants will be evaluated for the safety, clinical activity and toxicity. The primary end point was the objective response for each participant at the time of D-CIK and anti-PD-1 infusion as assessed by RECIST. Peripheral blood of patients were also assessed for related cytokine using ELISPOT assays. Additional,the investigators will evaluate tumor markers in participants with clinical response/non-response by immunohistochemical staining of tumor sections from previous diagnostic or therapeutic biopsy samples to determine the predictive biomarker that may be used in future studies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatocellular Carcinoma, Renal Cell Carcinoma, Bladder Cancer, Colorectal Cancer, Non-small-cell Lung Cancer, Breast Cancer

Keywords

Refractory solid tumors, Dendritic and Cytokine-induced killer cell, Anti-PD-1 antibody, Combination immunotherapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

D-CIK and anti-PD-1 Immunotherapy

Arm Type

Experimental

Arm Description

D-CIK was incubated with anti-PD-1 antibody before infused back into participants

Intervention Type

Biological

Intervention Name(s)

D-CIK and anti-PD-1 antibody

Intervention Description

Autologous dendritic and cytokine-induced killer cells (D-CIK)(1.0-1.5*10^10 cells)were incubated with anti-PD-1 antibody and infused into participants.

Primary Outcome Measure Information:

Title

Progress-free survival(PFS)

Description

PFS is defined as the time from the combined therapy until objective tumor progression or death.

Time Frame

12 Months

Secondary Outcome Measure Information:

Title

Overall survival (OS)

Description

OS is defined as the time from the combined therapy until death from any cause

Time Frame

12 Months

Title

Laboratory findings

Description

The number and secreted cytokines of CD3+ (or CD8+ or CD4+ or CD56+) T cells

Time Frame

6 Months

Title

Objective response rate

Description

The total number of Complete remission and Partial remission (According to the response criteria in solid tumor(RECIST))

Time Frame

12 Months

Title

Severity of adverse events

Description

According to National Cancer Institute Common Terminology Criteria for Adverse Events（NCI-CTCAE)

Time Frame

12 Months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Participantswith treatment-refractory advanced hepatocellular carcinoma, renal cell carcinoma,bladder cancer,colorectal cancer,non-small-cell lung cancer,breast cancer and other solid cancers. Age 18 to 75 years. Willing to sign a durable power of attorney. Able to understand and sign the Informed Consent Document. Life expectancy of greater than three months. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the preparative regimen. Adequate organ function. Serology: Seronegative for HIV antibody. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus. Hematology: WBC (> 3000/mm(3)). Platelet count greater than 100,000/mm(3). Hemoglobin greater than 8.0 g/dl. Chemistry: Serum ALT/AST less or equal to 2.5 times the upper limit of normal. Serum creatinine less than or equal to 1.6 mg/dl. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl. Exclusion Criteria: Previous treatment with anti-CTLA-4 and anti-PD-1/PD-L1. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). History of autoimmune disease Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). Concurrent antineoplastic therapies and systemic steroid therapy.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jian-Chuan Xia, Ph.D.

Phone

862087345699

xiajch@sysucc.org.cn

First Name & Middle Initial & Last Name or Official Title & Degree

Yi-Xin Zeng, Ph.D.

Phone

862087343333

zengYX@sysucc.org.cn

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yi-Xin Zeng, Ph.D.

Organizational Affiliation

Sun Yat-sen University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Sun Yat-Sen University, Cancer Center

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510060

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jian-Chuan Xia, Ph.D.

Phone

86-20-87345699

xiajch@sysucc.org.cn

First Name & Middle Initial & Last Name & Degree

Fang-jian Zhou, Ph.D.

Phone

86-20-87343404

zhoufj@sysucc.org.cn

First Name & Middle Initial & Last Name & Degree

Yi-Xin Zeng, Ph.D.

First Name & Middle Initial & Last Name & Degree

Jian-Chuan Xia, Ph.D.

First Name & Middle Initial & Last Name & Degree

Fang-jian Zhou, Ph.D.

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

22461641

Citation

Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012 Mar 28;4(127):127ra37. doi: 10.1126/scitranslmed.3003689.

Results Reference

result

PubMed Identifier

25747273

Citation

Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015 Jun;148(7):1383-91.e6. doi: 10.1053/j.gastro.2015.02.055. Epub 2015 Mar 4.

Results Reference

result

PubMed Identifier

26228759

Citation

Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015 Aug;14(8):561-84. doi: 10.1038/nrd4591.

Results Reference

result

PubMed Identifier

24668644

Citation

Pan K, Guan XX, Li YQ, Zhao JJ, Li JJ, Qiu HJ, Weng DS, Wang QJ, Liu Q, Huang LX, He J, Chen SP, Ke ML, Zeng YX, Xia JC. Clinical activity of adjuvant cytokine-induced killer cell immunotherapy in patients with post-mastectomy triple-negative breast cancer. Clin Cancer Res. 2014 Jun 1;20(11):3003-11. doi: 10.1158/1078-0432.CCR-14-0082. Epub 2014 Mar 25.

Results Reference

result

PubMed Identifier

26871284

Citation

Dai C, Lin F, Geng R, Ge X, Tang W, Chang J, Wu Z, Liu X, Lin Y, Zhang Z, Li J. Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer. Oncotarget. 2016 Mar 1;7(9):10332-44. doi: 10.18632/oncotarget.7243.

Results Reference

result

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A Study of Combinations of D-CIK Immunotherapy And Anti-PD-1 In Refractory Solid Tumors

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