Safety and Efficacy of iPD1 CD19 eCAR T Cells in Relapsed or Refractory B-cell Lymphoma

Pilot Study of Autologous Anti-CD19 4-1BB CAR T Cells With Cell-intrinsic PD1 Inhibition in Relapsed or Refractory B-cell Lymphoma

PD1 pathway is critical in determining the response to CAR T cell therapy. Emerging data suggested that Inhibition of PD1 could enhance the efficacy of CAR T cell therapy. iPD1 CD19 eCAR T cells is an enhanced version of the classical 2nd generation anti-CD19 4-1BB-costimulatory chimeric antigen receptor engineered T cells with cell-intrinsic PD1 inhibition by incorporation of a PD1 shRNA-expressing cassette in the CAR lentivector. This design will enhance the anti-tumor activities of CAR T cells by inhibiting PD1 induction after CAR T cell activation. This pilot, single arm, one center, dose-escalation, open label study is to determine the safety and efficacy of iPD1 CD19 eCAR T cells in relapsed or refractory CD19 positive lymphoma.

Subjects will be given a lymphodepletion chemotherapy comprised of Fludarabine and cyclophosphamide prior to CAR T cell infusion. The chemotherapy is completed 1 to 4 days before the first dost of iPD1 CD19 eCAR T cells.

Study Overview

• Status: Unknown
• Conditions: Relapsed or Refractory B-cell Lymphoma
• Intervention / Treatment: Biological: iPD1 CD19 eCAR T cells; Drug: Fludarabine and cyclophosphamide

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Zhitao Ying, MD; Email: yingzhitao001@163.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Beijing Cancer Hosptical
    • Contact: Zhitao Ying, MD; Email: yingzhitao001@163.com
    • Sub-Investigator: Zhitao Ying, MD
    • Sub-Investigator: Xiaoyu Xiang, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. CD19+ B cell lymphoma,verified by IHC or flow cytometry.
2. a prior history of at least one standard care of medication.
3. ineligible for allogeneic transplantation or relapsed after transplantation.
4. patients are 18 years older.
5. life expectancy > 3months.
6. ECOG ≤ 2.
7. satisfactory major organ functions: adequate heart function with LVEF≥50%; pulse oximetry of ≥ 90%; cockcroft-gault creatinine clearance≥40 ml/min; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3ULN; Bilirubin ≤2.0 mg/dl .
8. Blood: Hgb ≥ 80 g/L, ANC ≥ 1×10^9/L, PLT ≥ 50×10^9/L.
9. women of reproductive potential must have a negative pregnancy test. Male and female of reproductive potential must agree to use birth control during the study and one year post study.
10. measurable tumors.

Exclusion Criteria:

1. using immunosuppressive drugs or systemic steroids within one week of enrollment.
2. active infection.
3. HIV positive.
4. active hepatitis B virus infection or hepatitis C virus infection.
5. breastfeeding or pregnant women.
6. patients refuse to practice birth control during study and one year post study.
7. patients with a prior history of other malignances will be excluded from this study, but patients who have been cured from skin basal cell carcinoma or cervical cancer, or who have had their tumors removed by surgical resection but without further therapies and have more than 5 years of progression-free survival, can be included into the study.
8. currently enrolled in other study.
9. patients, in the opinion of investigators, may not be eligible or are not able to comply with the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: iPD1 CD19 eCAR T cells; patients will receive a lymphodepletion chemotherapy prior to CAR T cell infusion

Biological: iPD1 CD19 eCAR T cells; iPD1 CD19 eCAR T cells are administrated in a 3-day split-dose regimen （d0, 30%; d1, 30%; d2, 40%）. CAR T cell dose escalation: 1×10^5 /kg，1×10^6 /kg，3×10^6 /kg，and 6×10^6 CAR T cells/kg; Drug: Fludarabine and cyclophosphamide; Fludarabine 25 mg/m2 d1-3; cyclophosphamide 250 mg/m2 d1-3. Lymphodepletion chemotherapy is completed 1 to 4 days before CAR T cell infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety of infusion of iPD1 CD19 eCAR T cells as assessed by the incidents of treatment related adverse events per NCI CTCAE V4.0	incidents of treatment related adverse events per NCI CTCAE V4.0	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
treatment response	The efficacy of infusion of iPD1 CD19 eCAR T cells is assessed according to the standardized response criteria for malignant lymphoma (Cheson BD, JCO, 2007), which is defined as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).	6 months
overall survival	Overall survival is defined as the time from receiving iPD1 CD19 eCAR T cells infusion to death for any cause.	3 years
progression-free survival	Progression-free survival (PFS) is defined as the time from receiving iPD1 CD19 eCAR T cell infusion to disease progression or death from any cause.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistence of iPD1 CD19 eCAR T cells in patients	measured by quantitative PCR	2 years
proliferation of iPD1 CD19 eCAR T cells in patients	measured by flow cytometry	6 months

Collaborators and Investigators

• Sponsor: Peking University
• Collaborators: Marino Biotechnology Co., Ltd.
• Investigators: Study Director: Zhitao Ying, MD, Peking University Cancer Hospital & Institute; Study Director: Xiaoyu Xiang, PhD, Marino Biotechnology Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2017
• Primary Completion (Anticipated): June 1, 2019
• Study Completion (Anticipated): June 1, 2020

Study Registration Dates

• First Submitted: June 27, 2017
• First Submitted That Met QC Criteria: July 3, 2017
• First Posted (Actual): July 5, 2017

Study Record Updates

• Last Update Posted (Actual): September 14, 2017
• Last Update Submitted That Met QC Criteria: September 12, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 2017YJZ13

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No