Neoantigen Reactive T Cells Combined With SHR-1210 for Chinese Patients With Advanced Refractory Solid Tumors (NRT-01)

June 2, 2017 updated by: Zhengyun Zou, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Single Center Single Arm Clinical Prospective Study of Neoantigen Reactive T Cells (NRTs) Combined With Programmed Cell Death-1（PD-1） Inhibitor in the Treatment of Chinese Patients With Advanced Refractory Solid Tumors

The purpose of this study is to see the safety and efficient of neoantigen reactive T cells (NRTs) combined with programmed cell death-1(PD-1) inhibitor（SHR-1210）in the treatment of Chinese patients with advanced refractory solid tumors.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

The tumor-specific "none-self" immunogenic neoantigens encoded by either viral genes or somatic mutation genes, possess the potential to induce specific anti-cancer immunity, including cellular and humoral immune responses. Today, numerous clinical trials demonstrate that although these "none-self" antigens initiate the antigen-specific immunoglobulin G antibodies and cluster of differentiation 4（CD4）+/cluster of differentiation 8（CD8）+T-cells response, not all of them show a clinical benefit in the response rate, progression-free survival or overall survival.Immune tolerance induced by PD-1 or programmed cell death-ligand1（ PD-L1）maybe play a vital role for these negative outcomes.Personalized cell therapy plus checkpoint inhibitors maybe own a breakthrough in the treatment of those malignant diseases without standard options.Our center has successfully established a new method for preparing personalized neoantigen reactive T cells(NRTS) for adoptive cell therapy(ACT). Today, we will carry out a single center single arm clinical prospective study of NRTs combined with PD-1 inhibitor(SHR-1210) for the treatment of Chinese patients with advanced refractory solid tumors. Participants are assigned to receive 4 circles of cell therapy,and prior to each cycle's immunocytes treatment,preconditional chemotherapy and SHR-1210 will be carried out, and IL-2 continuous intravenous infusion（CIV） will also be given for 5 consecutive days after each time's cell infusion. The safety and clinical response rate（RR） are evaluated. Biomarkers and immunological markers are also monitored.

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Jiangsu
      • Nanjing, Jiangsu, China, 210008
        • Recruiting
        • The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Adult patients aged 18 to 75 years old
  • Histologic or cytologic confirmation of advanced refractory solid tumors with no available curative treatment options
  • At least one measurable disease: diameter ≥20mm or spiral computed tomography(CT)≥10mm; and can providing with tumor specimen (for testing the expression of PD -L1 and the infiltrating lymphocytes)
  • Must be human leukocyte antigen (HLA)-A2/A24/A11 positive
  • Eastern Cooperative Oncology Group(ECOG)<0-2 and expected survival time 3 months or more
  • At least one new antigen can induce T cell secrete interferon - gamma (IFN - gamma) twice as normal controls during the new antigens screening
  • Without anticancer treatment more than one month
  • Hematology Index including: Neutrophile granulocyte greater than 1.5×10^9/L; Hemoglobin greater than 10g/dL; Platelet greater than 100×10^9/L
  • Biochemical index including: Serum bilirubin not greater than 1.5x upper limit of reference range (ULN); glutamic-pyruvic transaminase（ALT） or glutamic-oxalacetic transaminase（AST） not greater than 2.5x ULN; Creatinine clearance no less than 60ml/min
  • Peripheral venous channel open and no contraindications to separating lymphocytes
  • Negative pregnancy test for women of childbearing potential, and patients must be willing to practice birth control during the regimen
  • Provision of informed consent
  • Be able to follow the research program and follow up process

Exclusion Criteria:

  • Those who now are undergoing other antitumor drug therapy (including chemotherapy, systemic steroids therapy, surgery, target therapy or immune therapy);
  • Prior treatment with PD-1 monoclonal antibody(mAb） or PD-L1 mAb;
  • Prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix;
  • History with pulmonary tuberculosis, and positive tests for Acquired Immune Deficiency Syndrome(HIV),hepatitis C virus(HCV),hepatitis B virus(HBV);
  • Patients with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, such as hypophysitis, pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism; Severe, uncontrolled medical condition that would affect patients' compliance or obscure the interpretation of toxicity determination or adverse events, including active severe infection, uncontrolled diabetes, angiocardiopathy (heart failure > class II New York Heart Association(NYHA), heart block >II grade, myocardial infarction, unstable arrhythmia or unstable angina within past 6 months, cerebral infarction within past 3 months) or pulmonary disease ( interstitial pneumonia, obstructive pulmonary disease or symptomatic bronchospasm).
  • Evidence with central nervous system(CNS) disease
  • Pregnant or nursing
  • Psychiatric medicines abuse without withdrawal, or history of psychiatric illness.
  • Hypersensitivity to investigational drugs or its components.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neoantigen Reactive T Cells + SHR-1210
Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5~1 x 10^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1（PD1） inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment.
Biological: Neoantigen Reactive T Cells(NRTs)
Neoantigen Reactive T Cells in an expected volume of 100 milliliter（mL） will be given by intravenous injection over 2-10 minutes through either a peripheral or a central line.
Biological: SHR-1210
SHR-1210 200mg will be administered as an intravenous infusion over 60 minutes.
Drug: Fludarabine
Fludarabine(FLU) 30mg/m2/d×3d，3 days prior to each NRTs infusion as preconditional chemotherapy.
Other Names:
  • FLU
Drug: Cyclophosphamide
Cyclophosphamide(CTX) 300mg/m2/d×3d，3 days prior to each NRTs infusion as preconditional chemotherapy.
Other Names:
  • CTX
Biological: Interleukin-2
Interleukin-2(IL-2)will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.
Other Names:
  • IL-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with Adverse Events
Time Frame: up to 6 months
using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients
up to 6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response Rate
Time Frame: At 3, 6 and 12 months
Response Rate（RR） will be evaluated according Response Evaluation Criteria in Solid Tumors
At 3, 6 and 12 months
Progression free survival (PFS)
Time Frame: At 6,9 and 12 months
the duration of progression free survival is measured from the time of treatment to the first date that recurrent or progressive disease or for any reason of death is objectively documented.
At 6,9 and 12 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: At 6,12 and 18 months
the duration is measured from the time of treatment to the time of death
At 6,12 and 18 months
Interferon-gama change of PBMC cells in the peripheral blood stimulated by tumor antigens
Time Frame: At baseline,40days,2 months,6 months and at the time of disease progress
T cells in the peripheral blood stimulated by tumor antigens for 24 hr，and then Interferon-gama secretion is measured
At baseline,40days,2 months,6 months and at the time of disease progress
Th1/Th2 change in the peripheral blood
Time Frame: At baseline,40days,2 months,6 months and at the time of disease progress
cytokines are measured by flow cytometry(FCM)
At baseline,40days,2 months,6 months and at the time of disease progress

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Investigators

  • Principal Investigator: Baorui Liu, M.D & Ph.D, The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2017

Primary Completion (Anticipated)

December 31, 2019

Study Completion (Anticipated)

December 31, 2020

Study Registration Dates

First Submitted

May 13, 2017

First Submitted That Met QC Criteria

May 26, 2017

First Posted (Actual)

May 31, 2017

Study Record Updates

Last Update Posted (Actual)

June 6, 2017

Last Update Submitted That Met QC Criteria

June 2, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NDTHNanjing

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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