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Dose-escalation Study of Safety of PBCAR20A in Subjects With r/r NHL or r/r CLL/SLL

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ClinicalTrials.gov Identifier: NCT04030195
Recruitment Status : Completed
First Posted : July 23, 2019
Results First Posted : January 31, 2023
Last Update Posted : January 31, 2023
Sponsor:
Information provided by (Responsible Party):
Precision BioSciences, Inc.

Study Description
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Brief Summary:
This is a Phase 1/2a, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study to evaluate the safety and clinical activity of PBCAR20A in adult subjects with r/r B-cell NHL or r/r CLL/SLL.

Condition or disease Intervention/treatment Phase
Non-Hodgkin's Lymphoma, Relapsed Chronic Lymphoid Leukemia in Relapse Non-Hodgkin's Lymphoma Refractory Chronic Lymphocytic Leukemia Lymphoma, Non-Hodgkin Leukemia, Lymphocytic, Chronic B-cell Chronic Lymphocytic Leukemia B-cell Non Hodgkin Lymphoma Small Lymphocytic Lymphoma Genetic: PBCAR20A Drug: Fludarabine Drug: Cyclophosphamide Phase 1 Phase 2

Detailed Description:
This is a multicenter, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study to evaluate safety, tolerability, clinical activity, and find an appropriate dose to optimize safety and efficacy of PBCAR20A in subjects with relapsed/refractory (r/r) CD20+ Non-Hodgkin Lymphoma (NHL) or r/r Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Before initiating PBCAR20A, therapy, subjects will be administered lymphodepletion chemotherapy composed of fludarabine and cyclophosphamide. At Day 0 of the Treatment Period, subjects will receive a single intravenous (IV) infusion of PBCAR20A. All subjects are monitored during the treatment period through Day 28. All subjects who receive a dose of PBCAR20A will be followed in a separate long-term follow-up (LTFU) study for 15 years after exiting this study.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Phase 1: Participants with r/r CD20+ B-cell NHL or r/r CLL/SLL will be enrolled to 3 escalating dose groups and treated sequentially, with the possibility of a single de-escalation. Within each dose group, at least 3 and at most 6 study participants will be treated with a single dose of PBCAR20A using a standard 3 + 3 design. The starting dose of PBCAR20A will be 1 × 10^6 chimeric antigen receptor (CAR) T cells/kg body weight. Subsequent dose groups will be treated with escalating doses to a maximum dose of 480 × 10^6 CAR T cells (flat dose). In the absence of dose-limiting toxicities (DLTs) (as described in Section 3.8 of the protocol), the dose will be increased using a fixed-dose scheme.

Phase 2: Study PBCAR20A-01 did not proceed into Phase 2.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2a, Open-label, Dose-escalation, Dose-expansion, Parallel Assignment Study to Evaluate the Safety and Clinical Activity of PBCAR20A in Subjects With Relapsed/Refractory (r/r) Non-Hodgkin Lymphoma (NHL) or r/r Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Actual Study Start Date : March 24, 2020
Actual Primary Completion Date : June 24, 2021
Actual Study Completion Date : June 24, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Fludarabine

Arms and Interventions
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Arm Intervention/treatment
Experimental: Dose Level 1 of PBCAR20A CAR T cells

1 x 10^6 chimeric antigen receptor (CAR) T cells per kg body weight.

In this study, PBCAR20A, allogeneic anti-cluster of differentiation (CD20) CAR T Cells, is used to treat patients with relapsed or refractory (r/r) CD20+ Non-Hodgkin Lymphoma (NHL) or r/r Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Route of Administration: Intravenous infusion (IV)

Lymphodepletion Conditioning: Lymphodepletion will be conducted several days prior to PBCAR20A infusion. A combination of fludarabine and cyclophosphamide will be used for lymphodepletion.

 Genetic: PBCAR20A
Single dose of Allogeneic Anti-CD20 CAR T cells will be infused, and a classic "3+3" dose escalation will be applied.
Other Name: Allogeneic Anti-CD20 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion (30 mg/m^2/day, Days -5 to -3).

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion (500 mg/m^2/day, Days -5 to -3).
Experimental: Dose Level 2 of PBCAR20A CAR T cells
240 x 10^6 CAR T cells (flat dose)
 Genetic: PBCAR20A
Single dose of Allogeneic Anti-CD20 CAR T cells will be infused, and a classic "3+3" dose escalation will be applied.
Other Name: Allogeneic Anti-CD20 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion (30 mg/m^2/day, Days -5 to -3).

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion (500 mg/m^2/day, Days -5 to -3).
Experimental: Dose Level 3 of PBCAR20A CAR T cells
480 x 10^6 CAR T cells (flat dose)
 Genetic: PBCAR20A
Single dose of Allogeneic Anti-CD20 CAR T cells will be infused, and a classic "3+3" dose escalation will be applied.
Other Name: Allogeneic Anti-CD20 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion (30 mg/m^2/day, Days -5 to -3).

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion (500 mg/m^2/day, Days -5 to -3).


Outcome Measures
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Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: Day 1 to Day 28 ]
    The maximum tolerated dose (MTD) is the dose level at which fewer than 33% of patients experience a dose limiting toxicity (DLT) using a 3+3 strategy.

  2. Number of Participants With Dose-Limiting Toxicities [ Time Frame: 1 year ]
    Dose-limiting toxicities (DLT) are certain Grade 3 and Grade 4 toxic reactions as defined by the protocol and CTCAE v5.0.


Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: 1 year ]
    Objective response rate (ORR) is a measure of clinical activity as response in NHL by the revised Lugano Classification (Cheson et al, 2016) or a response in CLL/SLL by the International Workshop on Chronic Lymphocytic Leukemia 2018 guidelines.

  2. Progression-free Survival (PFS) [ Time Frame: 1 year ]
    Progression-free survival is defined as the duration (days) from Day 0 to disease progression or death.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria

Criteria for NHL:

  • r/r CD20+ B-cell NHL that is histologically confirmed by archived tumor biopsy tissue from the last relapse and corresponding pathology report.
  • Measurable or detectable disease according to the Lugano classification.
  • Primary refractory disease or r/r disease after a response to 2 prior regimens.

Criteria for CLL/SLL:

  • Diagnosis of CD20+ CLL with indication for treatment based on the iwCLL guidelines and clinically measurable disease or SLL with measurable disease that is biopsy-proven SLL.
  • Previously failed/tolerant to at least 2 prior lines of systemic targeted therapy of known benefit.

Criteria for both NHL and CLL/SLL:

  • Study participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
  • Study participant has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function.

Key Exclusion Criteria:

Criteria for NHL:

  • Requirement for urgent therapy due to mass effects such as bowel obstruction, spinal cord, or blood vessel compression.
  • Active central nervous system (CNS) disease. A negative computed tomography (CT)/magnetic resonance imaging (MRI) is required at Screening if the study participant has a history of CNS lymphoma.

Criteria for NHL and CLL/SLL:

  • Active CNS disease. A negative lumbar puncture is required at Screening if the study participant has a history of CNS disease.
  • Previous malignancy, besides the malignancies of inclusion (B-cell NHL or CLL/SLL), that in the investigator's opinion, has a high risk of relapse in the next 2 years.
  • Active uncontrolled fungal, bacterial, viral, protozoal, or other infection.
  • Any form of primary immunodeficiency.
  • History of human immunodeficiency virus (HIV) infection.
  • Active hepatitis B or C.
  • Uncontrolled cardiovascular disease.
  • Hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening.
  • Presence of a CNS disorder that renders ineligible for treatment.
  • History of a genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman Diamond syndrome, or any other known bone marrow failure syndrome.
  • Received ASCT within 45 days of Screening if the study participant has met the rest of the count requirements.
  • Must not have received systemic corticosteroid therapy for at least 7 days prior to initiating lymphodepletion chemotherapy.
  • Received a live vaccine within 4 weeks before Screening.
  • Radiotherapy within 4 weeks determined on a case-by-case basis.
  • Presence of a pleural/peritoneal/pericardial catheter.
  • Current use of any anticoagulant or antiplatelet therapy.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04030195


Locations
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United States, California
City of Hope
Duarte, California, United States, 91010
Stanford University
Stanford, California, United States, 94305
United States, New York
Columbia University
New York, New York, United States, 10032
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Precision BioSciences, Inc.
Investigators
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Study Chair: Alan List, MD Precision BioSciences, Inc.
  Study Documents (Full-Text)

Documents provided by Precision BioSciences, Inc.:
Study Protocol  [PDF] February 10, 2021
Statistical Analysis Plan  [PDF] March 29, 2022

More Information
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Responsible Party: Precision BioSciences, Inc.
ClinicalTrials.gov Identifier: NCT04030195    
Other Study ID Numbers: PBCAR20A-01
First Posted: July 23, 2019    Key Record Dates
Results First Posted: January 31, 2023
Last Update Posted: January 31, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
 Leukemia, B-Cell
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists