B-cell Chronic Lymphocytic Leukemia, B-cell Non Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Chronic Lymphoid Leukemia in Relapse, Leukemia, Lymphocytic, Chronic, Lymphoma, Non-Hodgkin, Non-Hodgkin's Lymphoma Refractory, Non-Hodgkin's Lymphoma, Relapsed, Small Lymphocytic Lymphoma
Conditions
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.
Interventions
GENETICPBCAR20A
Single dose of Allogeneic Anti-CD20 CAR T cells will be infused, and a classic 3+3 dose escalation will be applied.
DRUGFludarabine
Fludarabine is used for lymphodepletion (30 mg/m\^2/day, Days -5 to -3).
DRUGCyclophosphamide
Cyclophosphamide is used for lymphodepletion (500 mg/m\^2/day, Days -5 to -3).
Sponsors
Precision BioSciences, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 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. |
| Number of Participants With Dose-Limiting Toxicities | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 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. |
| Progression-free Survival (PFS) | 1 year | Progression-free survival is defined as the duration (days) from Day 0 to disease progression or death. |
Countries
United States
Participant flow
Pre-assignment details
20 participants were screened for this study, of whom 2 screen failed.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 of PBCAR20A CAR T Cells 1 x 10\^6 CAR T cells per kg body weight | 8 |
| Dose Level 2 of PBCAR20A CAR T Cells 240 x 10\^6 CAR T cells (flat dose) | 3 |
| Dose Level 3 of PBCAR20A CAR T Cells 480 x 10\^6 CAR T cells (flat dose) | 6 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Dose Level 1 of PBCAR20A CAR T Cells | Dose Level 2 of PBCAR20A CAR T Cells | Dose Level 3 of PBCAR20A CAR T Cells |
|---|---|---|---|---|
| Age, Continuous | 56.24 years STANDARD_DEVIATION 15.85 | 58.25 years STANDARD_DEVIATION 17.07 | 47.00 years STANDARD_DEVIATION 19.08 | 58.17 years STANDARD_DEVIATION 13.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 7 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 7 Participants | 2 Participants | 5 Participants |
| Region of Enrollment United States | 17 participants | 8 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 14 Participants | 6 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 8 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 8 / 8 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 3 / 8 | 0 / 3 | 1 / 6 |
Outcome results
Primary
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.
Time frame: Day 1 to Day 28
Population: All participants. The participant who was dosed twice at Dose Level 3 (DL3) was counted as 2 individual participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PBCAR20A CAR T Cells | Maximum Tolerated Dose (MTD) | NA 10^6 CAR T cells |
Primary
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.
Time frame: 1 year
Population: All participants. The participant who was dosed twice at DL3 was counted as 2 individual participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBCAR20A CAR T Cells | Number of Participants With Dose-Limiting Toxicities | 1 Participants |
| Dose Level 2 of PBCAR20A CAR T Cells | Number of Participants With Dose-Limiting Toxicities | 0 Participants |
| Dose Level 3 of PBCAR20A CAR T Cells | Number of Participants With Dose-Limiting Toxicities | 0 Participants |
Secondary
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.
Time frame: 1 year
Population: All participants. The participant who was dosed twice at DL3 was counted as 2 individual participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PBCAR20A CAR T Cells | Objective Response Rate | Partial Response | 1 Participants |
| PBCAR20A CAR T Cells | Objective Response Rate | Complete Response | 1 Participants |
| PBCAR20A CAR T Cells | Objective Response Rate | Non-responders | 6 Participants |
| PBCAR20A CAR T Cells | Objective Response Rate | Responders | 2 Participants |
| Dose Level 2 of PBCAR20A CAR T Cells | Objective Response Rate | Complete Response | 0 Participants |
| Dose Level 2 of PBCAR20A CAR T Cells | Objective Response Rate | Non-responders | 2 Participants |
| Dose Level 2 of PBCAR20A CAR T Cells | Objective Response Rate | Responders | 1 Participants |
| Dose Level 2 of PBCAR20A CAR T Cells | Objective Response Rate | Partial Response | 1 Participants |
| Dose Level 3 of PBCAR20A CAR T Cells | Objective Response Rate | Responders | 3 Participants |
| Dose Level 3 of PBCAR20A CAR T Cells | Objective Response Rate | Non-responders | 4 Participants |
| Dose Level 3 of PBCAR20A CAR T Cells | Objective Response Rate | Partial Response | 3 Participants |
| Dose Level 3 of PBCAR20A CAR T Cells | Objective Response Rate | Complete Response | 0 Participants |
Secondary
Progression-free Survival (PFS)
Progression-free survival is defined as the duration (days) from Day 0 to disease progression or death.
Time frame: 1 year
Population: All participants. The participant who was dosed twice at DL3 was counted as 2 individual participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PBCAR20A CAR T Cells | Progression-free Survival (PFS) | 29.5 Days |
| Dose Level 2 of PBCAR20A CAR T Cells | Progression-free Survival (PFS) | 29.0 Days |
| Dose Level 3 of PBCAR20A CAR T Cells | Progression-free Survival (PFS) | 29.0 Days |