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

NCT03171220 | Unknown Phase 1

• 1 other identifier: NDTHNanjing
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Advanced Malignant Solid Tumor

Keywords

Neoantigen; Neoantigen Reactive T cells (NRTs); PD-1 Inhibitor; Advanced Solid Tumor; Adoptive Cell Therapy(ACT); PD-1 antibody; SHR1210

Outcome Measures

Primary Outcomes (1)

• Number of participants with Adverse Events

  using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients

  up to 6 months

Secondary Outcomes (2)

• Response Rate

  At 3, 6 and 12 months

• Progression free survival (PFS)

  At 6,9 and 12 months

Other Outcomes (3)

• Overall Survival (OS)

  At 6,12 and 18 months

• Interferon-gama change of PBMC cells in the peripheral blood stimulated by tumor antigens

  At baseline,40days,2 months,6 months and at the time of disease progress

• Th1/Th2 change in the peripheral blood

  At baseline,40days,2 months,6 months and at the time of disease progress

Study Arms (1)

Neoantigen Reactive T Cells + SHR-1210

EXPERIMENTAL

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); Biological: SHR-1210; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Interleukin-2

Interventions

Neoantigen Reactive T Cells(NRTs) BIOLOGICAL

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.

Neoantigen Reactive T Cells + SHR-1210

SHR-1210 BIOLOGICAL

SHR-1210 200mg will be administered as an intravenous infusion over 60 minutes.

Neoantigen Reactive T Cells + SHR-1210

Fludarabine DRUG

Fludarabine(FLU) 30mg/m2/d×3d，3 days prior to each NRTs infusion as preconditional chemotherapy.

Also known as: FLU

Neoantigen Reactive T Cells + SHR-1210

Cyclophosphamide DRUG

Cyclophosphamide(CTX) 300mg/m2/d×3d，3 days prior to each NRTs infusion as preconditional chemotherapy.

Also known as: CTX

Neoantigen Reactive T Cells + SHR-1210

Interleukin-2 BIOLOGICAL

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.

Also known as: IL-2

Neoantigen Reactive T Cells + SHR-1210

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School: lead

Study Sites (1)

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University

Nanjing, Jiangsu, 210008, China

RECRUITING

Related Publications (8)

• Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, Prickett TD, Gartner JJ, Crystal JS, Roberts IM, Trebska-McGowan K, Wunderlich JR, Yang JC, Rosenberg SA. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016 Apr;22(4):433-8. doi: 10.1038/nm.4051. Epub 2016 Feb 22.

  PMID: 26901407 RESULT

• Desrichard A, Snyder A, Chan TA. Cancer Neoantigens and Applications for Immunotherapy. Clin Cancer Res. 2016 Feb 15;22(4):807-12. doi: 10.1158/1078-0432.CCR-14-3175. Epub 2015 Oct 29.

  PMID: 26515495 RESULT

• Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8. doi: 10.1126/science.aaa4967.

  PMID: 25838374 RESULT

• Su S, Zou Z, Chen F, Ding N, Du J, Shao J, Li L, Fu Y, Hu B, Yang Y, Sha H, Meng F, Wei J, Huang X, Liu B. CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer. Oncoimmunology. 2016 Nov 22;6(1):e1249558. doi: 10.1080/2162402X.2016.1249558. eCollection 2017.

  PMID: 28197365 RESULT

• Stevanovic S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, Robins HS, Robbins PF, Klebanoff CA, Rosenberg SA, Hinrichs CS. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017 Apr 14;356(6334):200-205. doi: 10.1126/science.aak9510.

  PMID: 28408606 RESULT

• Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016 Dec 8;375(23):2255-2262. doi: 10.1056/NEJMoa1609279.

  PMID: 27959684 RESULT

• Parkhurst M, Gros A, Pasetto A, Prickett T, Crystal JS, Robbins P, Rosenberg SA. Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression. Clin Cancer Res. 2017 May 15;23(10):2491-2505. doi: 10.1158/1078-0432.CCR-16-2680. Epub 2016 Nov 8.

  PMID: 27827318 RESULT

• Chen F, Zou Z, Du J, Su S, Shao J, Meng F, Yang J, Xu Q, Ding N, Yang Y, Liu Q, Wang Q, Sun Z, Zhou S, Du S, Wei J, Liu B. Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors. J Clin Invest. 2019 Mar 5;129(5):2056-2070. doi: 10.1172/JCI99538. Print 2019 May 1.

  PMID: 30835255 DERIVED

MeSH Terms

Interventions

camrelizumab; fludarabine; Cyclophosphamide; Interleukin-2

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Baorui Liu, M.D & Ph.D

  The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Baorui Liu, M.D & Ph.D

CONTACT

+86-25-83304616; baoruiliu@nju.edu.cn

Zhengyun Zou, M.D & Ph.D

CONTACT

+86-25-83304616; zouzhengyun@medmail.com.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief physician

Study Record Dates

• First Submitted: May 13, 2017
• First Posted: May 31, 2017
• Study Start: June 1, 2017
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2020
• Last Updated: June 6, 2017

Record last verified: 2017-06

Locations

CN (1)