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

Study Overview
=================
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.

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.

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)

Conditions
-----------------
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

Intervention / Treatment
-----------------
* Genetic: PBCAR20A
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1 of PBCAR20A CAR T cells<br>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<br>* Single dose of Allogeneic Anti-CD20 CAR T cells will be infused, and a classic 3+3 dose escalation will be applied.<br>* Other names: Allogeneic Anti-CD20 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion (30 mg/m^2/day, Days -5 to -3).<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion (500 mg/m^2/day, Days -5 to -3).<br>|
| Experimental: Dose Level 2 of PBCAR20A CAR T cells<br>240 x 10^6 CAR T cells (flat dose) | Genetic: PBCAR20A<br>* Single dose of Allogeneic Anti-CD20 CAR T cells will be infused, and a classic 3+3 dose escalation will be applied.<br>* Other names: Allogeneic Anti-CD20 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion (30 mg/m^2/day, Days -5 to -3).<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion (500 mg/m^2/day, Days -5 to -3).<br>|
| Experimental: Dose Level 3 of PBCAR20A CAR T cells<br>480 x 10^6 CAR T cells (flat dose) | Genetic: PBCAR20A<br>* Single dose of Allogeneic Anti-CD20 CAR T cells will be infused, and a classic 3+3 dose escalation will be applied.<br>* Other names: Allogeneic Anti-CD20 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion (30 mg/m^2/day, Days -5 to -3).<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion (500 mg/m^2/day, Days -5 to -3).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | 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. | Day 1 to Day 28 | 
| Number of Participants With Dose-Limiting Toxicities | Dose-limiting toxicities (DLT) are certain Grade 3 and Grade 4 toxic reactions as defined by the protocol and CTCAE v5.0. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | 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. | 1 year | 
| Progression-free Survival (PFS) | Progression-free survival is defined as the duration (days) from Day 0 to disease progression or death. | 1 year |