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出境医 / 临床实验 / Dose-escalation Study of Safety of PBCAR20A in Subjects With r/r NHL or r/r CLL/SLL
Dose-escalation Study of Safety of PBCAR20A in Subjects With r/r NHL or r/r CLL/SLL
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.
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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 :
- 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.
- 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 :
- 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:
- 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.
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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: | Monika Vainorius, MD | Precision BioSciences, Inc. |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | July 19, 2019 | ||||
| First Posted Date ICMJE | July 23, 2019 | ||||
| Last Update Posted Date | April 29, 2021 | ||||
| Actual Study Start Date ICMJE | March 24, 2020 | ||||
| Estimated Primary Completion Date | March 2022 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
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| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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.
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||
| Current Other Pre-specified Outcome Measures |
Area Under the Curve [AUC] [ Time Frame: 1 year ] To evaluate Area Under the Curve [AUC] of PBCAR20A in patients tested.
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| Original Other Pre-specified Outcome Measures | Same as current | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Dose-escalation Study of Safety of PBCAR20A in Subjects With r/r NHL or r/r CLL/SLL | ||||
| Official Title ICMJE | 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) | ||||
| 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). | ||||
| 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 Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 1 Phase 2 |
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| Study Design ICMJE | 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. Primary Purpose: Treatment |
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| Condition ICMJE |
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| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Recruiting | ||||
| Estimated Enrollment ICMJE |
90 | ||||
| Original Estimated Enrollment ICMJE | Same as current | ||||
| Estimated Study Completion Date ICMJE | February 2023 | ||||
| Estimated Primary Completion Date | March 2022 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Key Inclusion Criteria* Criteria for NHL:
Criteria for CLL/SLL:
Criteria for both NHL and CLL/SLL:
Key Exclusion Criteria*: Criteria for NHL:
Criteria for CLL/SLL:
Criteria for NHL and CLL/SLL:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | No | ||||
| Contacts ICMJE |
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| Listed Location Countries ICMJE | United States | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT04030195 | ||||
| Other Study ID Numbers ICMJE | PBCAR20A-01 | ||||
| Has Data Monitoring Committee | No | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Precision BioSciences, Inc. | ||||
| Study Sponsor ICMJE | Precision BioSciences, Inc. | ||||
| Collaborators ICMJE | Not Provided | ||||
| Investigators ICMJE |
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| PRS Account | Precision BioSciences, Inc. | ||||
| Verification Date | April 2021 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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