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

• ClinicalTrials.gov Identifier: NCT04030195
• Recruitment Status: Completed
• First Posted: July 23, 2019
• Last Update Posted: June 24, 2022
• Sponsor: Precision BioSciences, Inc.
• Information provided by (Responsible Party): Precision BioSciences, Inc.

Study Description

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 (Cohort A) or r/r CLL/SLL (Cohort B).

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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

Phase 1: In each cohort, r/r CD20+ B-cell NHL (Cohort A) or r/r CLL/SLL (Cohort B), 3 escalating dose groups will be enrolled 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

Arms and Interventions

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

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) [ Time Frame: Day 1 - Day 28 ]
   To determine the maximum tolerated dose (MTD), which is defined as 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 Toxicity(ies) [ Time Frame: 1 year ]
   To assess adverse events as dose limiting toxicities as defined by the protocol and CTCAE v5.0.

Secondary Outcome Measures :

1. Objective Response Rate of Patients [ Time Frame: 1 year ]
   To assess clinical activity as response in B-ALL by the NCCN Guidelines on ALL (NCCN, 2017) and in NHL by the revised Lugano Classification (Cheson et al, 2016), both reported as objective response rate.

Other Outcome Measures:

1. Area Under the Curve [AUC] [ Time Frame: 1 year ]
   To evaluate Area Under the Curve [AUC] of PBCAR20A in patients tested.

Eligibility Criteria

• 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

Locations

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

• Study Chair: Alan List, MD; Precision BioSciences, Inc.

More Information

• Responsible Party: Precision BioSciences, Inc.
• ClinicalTrials.gov Identifier: NCT04030195
• Other Study ID Numbers: PBCAR20A-01
• First Posted: July 23, 2019
• Last Update Posted: June 24, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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