Study of CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell

NCT03019055 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: PRO00028724
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 1/1b, interventional single arm, open label, treatment study designed to evaluate the safety and feasibility of infusion of autologous T cells engineered to contain an anti-cluster of differentiation 19 (CD19) and anti-cluster of differentiation 20 (CD20) single chain variable fragment (scFv) coupled to cluster of differentiation CD3ζ (CD3ζ) and co-stimulatory domain 4-1BB (4-1BB) signaling domains in patients with relapsed and/or refractory CD19 or CD20 positive B cell malignancies

Conditions

Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Keywords

CAR-T; Chimeric antigen receptor T-cell therapy; CAR Therapy

Outcome Measures

Primary Outcomes (1)

• Number of Adverse Events After CAR 20/19-T Cell Infusion

  This measure is the number of adverse events with grade 3 to 5 severity per Common Terminology Criteria for Adverse Events (ver. 4.03) occurring within the first 28 days following infusion.

  28 days after infusion

Study Arms (4)

CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg)

EXPERIMENTAL

Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.

Biological: CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg)

CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg)

EXPERIMENTAL

Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.

Biological: CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg)

CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg)

EXPERIMENTAL

Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.

Biological: CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg)

CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg)

EXPERIMENTAL

Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.

Biological: CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg)

Interventions

CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg) BIOLOGICAL

CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 0: 2.5 x10\^5 CAR-20/19-T cells/kg (starting dose level)

CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg)

CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg) BIOLOGICAL

CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 1: 7.5 x10\^5 CAR-20/19-T cells/kg

CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg)

CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg) BIOLOGICAL

CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 2: 2.5 x10\^6 CAR-20/19-T cells/kg (goal cell dose) Phase 1b Expansion Dose Level: 2.5 x 10\^6 cells/kg (single infusion)

CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg)

CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg) BIOLOGICAL

CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection.

CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) / small lymphocytic leukemia (SLL): Patients must be aged≥18 years with relapsed, refractory disease and no available curative options that meet clinical criteria to initiate treatment.
• Patients with B-cell NHL or CLL/SLL must have either CD19 or CD20 positive disease on most recent biopsy performed (a repeat biopsy is not mandatory for this study except as noted below). A minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry on prior or repeat biopsy is required.
• Absolute CD3+ T cell count ≥50/mm\^3.
• MRI brain and Lumbar Puncture with cerebral spinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement only in patients with history of CNS involvement.
• Measurable disease must have been documented within 4 weeks of the time of consent defined as the following by disease specific subtype:
• B-cell NHL: Active disease defined as nodal lesions greater than 20 mm in the long axis or extranodal lesions \>10 mm in long and short axis or bone marrow involvement that is biopsy proven.
• CLL/SLL: Active disease by either bone marrow, peripheral flow cytometry, or CT and/or positron emission tomography (PET) imaging with nodal disease.
• Patients should have failed at least two lines of a standard treatment and meet disease specific criteria detailed below:
• CLL/SLL: measurable disease as defined above that has relapsed after at least one line of chemo-immunotherapy and progressed or intolerant to ibrutinib monotherapy.
• CD19 or CD20 positive B cell NHL limited to the following histologies: Advanced Stage III or IV Follicular Lymphoma, Diffuse Large B cell Lymphoma and associated subtypes (e.g. aggressive B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein Barr virus positive diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone lymphoma, and Richter's transformation) and Mantle cell lymphoma. Specific criteria include:
• Patients must have active, measurable disease after two lines of cytotoxic chemotherapy of which one must be anthracycline containing.
• Must have received Rituximab or another CD20 antibody and at minimum two chemotherapy regimens appropriate for their disease.
• Either failed autologous transplant or ineligible to receive autologous transplant
• Karnofsky performance score ≥70. See Appendix A for scales.
• Normal Baseline Neurological Evaluation: Mini-Mental Status Exam Score 24-30.

You may not qualify if:

• Positive beta-human chorionic gonadotropin in females of child-bearing potential.
• Patients with known systemic allergy to bovine or murine products.
• Known prior positive serology for human anti-mouse antibody (HAMA).
• Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.
• History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon: such as systemic lupus erythematous, Wegner's glomerulonephritis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (AIHA, ITP) requiring steroid therapy defined as \>20 mg of prednisone or equivalent daily.
• Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
• Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of ≥4 weeks required from administration of any other investigational agents on other clinical trials prior to enrollment on this CAR-T protocol.
• Refusal to participate in the long-term follow-up protocol.
• Patients with active CNS involvement by malignancy on MRI or by lumbar puncture.
• a. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was \>4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.
• Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are \<100 days' post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
• Previous CAR-T cell therapy directed at either CD19 or CD20 within 100 days of planned CAR-20/19-T cell infusion (does not include re-enrollment)
• a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry.
• Anti-CD20 antibody treatment within 4 weeks of cell infusion.
• Anti-CD19 antibody treatment within 4 weeks of cell infusion.

Sponsors & Collaborators

• Medical College of Wisconsin: lead
• Children's Hospital and Health System Foundation, Wisconsin: collaborator

Study Sites (1)

Froedtert Hospital & Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (4)

• Zurko JC, Fenske TS, Johnson BD, Bucklan D, Szabo A, Xu H, Chaney K, Hamadani M, Hari P, Shah NN. Long-term outcomes and predictors of early response, late relapse, and survival for patients treated with bispecific LV20.19 CAR T-cells. Am J Hematol. 2022 Dec;97(12):1580-1588. doi: 10.1002/ajh.26718. Epub 2022 Sep 20.

  PMID: 36068950 DERIVED

• Knight JM, Szabo A, Arapi I, Wu R, Emmrich A, Hackett E, Sauber G, Yim S, Johnson B, Hari P, Schneider D, Dropulic B, Cusatis RN, Cole SW, Hillard CJ, Shah NN. Patient-reported outcomes and neurotoxicity markers in patients treated with bispecific LV20.19 CAR T cell therapy. Commun Med (Lond). 2022 May 12;2(1):49. doi: 10.1038/s43856-022-00116-5. eCollection 2022.

  PMID: 35603278 DERIVED

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

  PMID: 34515338 DERIVED

• Shah NN, Johnson BD, Schneider D, Zhu F, Szabo A, Keever-Taylor CA, Krueger W, Worden AA, Kadan MJ, Yim S, Cunningham A, Hamadani M, Fenske TS, Dropulic B, Orentas R, Hari P. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020 Oct;26(10):1569-1575. doi: 10.1038/s41591-020-1081-3. Epub 2020 Oct 5.

  PMID: 33020647 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Nirav Shah, MD
• Organization: Froedtert Hospital and the Medical College of Wisconsin

cccto@mcw.edu

414-805-8900

Study Officials

• Nirav Shah, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: The study is divided into two phases. Phase 1 and Phase 1b. Phase 1: consists of 2 cohorts; dose escalation and dose expansion. The CAR-T cells were given over 2 days. In the phase 1 portion, there will be a dose escalation cohort to determine the safe CAR-20/19-T cell dose in patients with CLL/SLL and NHL. Once the desired dose has been identified there will be a 6 patient dose expansion phase at the specified dose level. Phase 1b: In the Phase 1b portion of the study, we will test the safety of unfractionated CAR-T cells utilizing the safe dose identified in the phase 1 portion (2.5 x 10\^6 cells/kg).

Study Record Dates

• First Submitted: January 5, 2017
• First Posted: January 12, 2017
• Study Start: October 16, 2017
• Primary Completion: October 1, 2019
• Study Completion: August 24, 2021
• Last Updated: July 27, 2023
• Results First Posted: May 7, 2021

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)