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

• ClinicalTrials.gov Identifier: NCT04030195
• Recruitment Status: Recruiting
• First Posted: July 23, 2019
• Last Update Posted: November 2, 2020
• 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 study participants 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 the safety and tolerability, find an appropriate dose to optimize safety and efficacy, and evaluate 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). Before initiating PBCAR20A, 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)
• Estimated Enrollment: 90 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

Part 1: In each cohort, 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 3 × 10^5 CAR T cells/kg body weight. Subsequent dose groups will be treated with escalating doses to a maximum dose of 3 × 10^6 CAR T cells/kg. In the absence of DLTs (as described in Section 3.7), the dose will be increased using a fixed-dose scheme.

Part 2: Upon the determination of the MTDs for Cohorts A and B, these respective doses will be used in the dose-expansion part, in which additional study participants will be enrolled and treated. Study participants in the expanded cohorts will be treated with a single dose of PBCAR20A.

• 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 Study Participants 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
• Estimated Primary Completion Date: March 2022
• Estimated Study Completion Date: February 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Level 1 of PBCAR20A CAR T cells; 1 x 10^6 CAR T cells per kg body weight. In this study, PBCAR20A, allogeneic anti-CD20 CAR T Cells, is used to treat patients with relapsed or refractory (r/r) Non-Hodgkin Lymphoma (NHL) or r/r Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Route of Administration: Intravenous infusion. 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.; Drug: Cyclophosphamide; Cyclophosphamide is used for lymphodepletion.
Experimental: Dose Level 2 of PBCAR20A CAR T cells; 3 x 10^6 CAR T cells per kg body weight.	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.; Drug: Cyclophosphamide; Cyclophosphamide is used for lymphodepletion.
Experimental: Dose Level 3 of PBCAR20A CAR T cells; 6 x 10^6 CAR T cells per kg body weight.	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.; Drug: Cyclophosphamide; Cyclophosphamide is used for lymphodepletion.

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 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 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 CLL/SLL:

• Active CNS disease. A negative lumbar puncture is required at Screening if the study participant has a history of CNS disease.

Criteria for NHL and CLL/SLL:

• 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.
• Active hemolytic anemia.
• 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 1 day prior to initiating lymphodepletion chemotherapy.
• Received a systemic biologic agent within 30 days or 5 half-lives.
• Received a live vaccine within 4 weeks before Screening.
• Received standard cytotoxic chemotherapy within 10 days of 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.

  • Additional criteria apply

Contacts and Locations

Contacts

Contact: Clinical Precision BioSciences, Inc.; 919-314-5512; clinical@precisionbiosciences.com

Locations

United States, California

City of Hope; Recruiting

Duarte, California, United States, 91010

Contact: Geoffrey Shouse, MD 800-826-4673

Principal Investigator: Geoffrey Shouse, MD

Stanford University; Recruiting

Stanford, California, United States, 94305

Contact: David Miklos, MD 650-498-6000

Principal Investigator: David Miklos, MD

United States, New York

Columbia University; Recruiting

New York, New York, United States, 10032

Contact: Ran Reshef, MD 212-305-5098

Principal Investigator: Ran Reshef, MD

United States, Ohio

Cleveland Clinic; Recruiting

Cleveland, Ohio, United States, 44195

Contact: Brian Hill, MD, PhD 216-445-9451

Principal Investigator: Brian Hill, MD, PhD

United States, Texas

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Sattva Neelapu, MD 713-792-2860

Principal Investigator: Sattva Neelapu, MD

Sponsors and Collaborators

Precision BioSciences, Inc.

Investigators

• Study Chair: Chris Heery, MD; Chief Medical Officer

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: November 2, 2020
• Last Verified: October 2020

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