Dose-escalation, Dose-expansion Study of Safety of PBCAR0191 in Patients With r/r NHL and r/r B-cell ALL

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/2a, nonrandomized, open-label, parallel assignment, dose-escalation, and dose-optimization study to evaluate the safety and clinical activity of PBCAR0191 in adults with r/r B ALL (Cohort A) and in adults with r/r B-cell NHL (Cohort N) and identify a treatment regimen most likely to result in clinical efficacy while maintaining a favorable safety profile.

Detailed Description
-----------------
This is a multicenter, nonrandomized, open-label, parallel assignment, dose-escalation, and dose-optimization study to evaluate the safety and tolerability, find an appropriate dose to optimize safety and efficacy, and evaluate clinical activity of PBCAR0191 in subjects with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL). Before initiating PBCAR0191, subjects will be administered lymphodepletion chemotherapy composed of fludarabine and cyclophosphamide. At Day 0 of the Treatment Period, subjects will receive an intravenous (IV) infusion of PBCAR0191. All subjects are monitored during the treatment period through Day 28. All subjects who receive a dose of PBCAR0191 will be followed in a separate long-term follow-up (LTFU) study for up to15 years after exiting this study.

Official Title
-----------------
Phase 1/2a, Open-label, Dose-escalation, Dose-expansion, Parallel Assignment Study to Evaluate Safety and Clinical Activity of PBCAR0191 in Subjects With Relapsed/Refractory (r/r) Non-Hodgkin Lymphoma (NHL) and r/r B-cell Acute Lymphoblastic Leukemia (B-ALL)

Conditions
-----------------
Non-Hodgkin Lymphoma, B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Genetic: PBCAR0191
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria* Criteria for B-ALL: Subject has unequivocal r/r CD19+ B-ALL that has been confirmed by morphology, flow cytometry, or a validated minimal residual disease assay. Subjects with Philadelphia chromosome positive disease can be eligible if they are intolerant to tyrosine kinase inhibitor therapy or if they have r/r disease. Criteria for NHL: Subject has unequivocal aggressive CD19+ r/r B-cell NHL that is confirmed by archived tumor biopsy tissue from last relapse after CD19-directed therapy and corresponding pathology report. Alternatively, if at least 1 tumor involved site is accessible at time of Screening, the subject's diagnosis is confirmed by pretreatment biopsy (excisional when possible) or by flow cytometry of fine needle aspirate. If a subject never had a CR, a sample from the most recent biopsy is acceptable. NHL subtypes included but are not limited to: Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation FL including Grade 3 or transformed FL High-grade B-cell lymphoma Primary mediastinal lymphoma Subject has measurable or detectable (for example positron emission tomography-positive) disease according to the Lugano Classification. Subject must have received at least 2 prior chemotherapy-containing regimens, consistent with standard of care treatment guidance (e.g., NCCN), unless no second line therapy of known benefit exists for a given subject. Other than those specifically prohibited, other therapies are allowed until 7 days prior to initiation of LD. In that case, all Screening safety laboratories and disease assessments must be performed after the last dose of prior therapy. For Richter's transformation, only 1 prior line of therapy is required for the DLBCL component. Subject has received no more than 7 systemic lines of anti-cancer therapy for the disease under study. Subjects previously treated with CD19-directed autologous CAR T therapies have received no more than 2 lines of therapy after administration of their previous CAR T product. Expansion cohort only: Subjects must have received autologous CD19-directed CAR T therapy and demonstrated clinical response to the treatment at Day 28 or later, followed by relapse. Criteria for both B-ALL and NHL: Eastern Cooperative Oncology Group performance status score of 0 or 1. An estimated life expectancy of at least 12 weeks according to the investigator's judgment. Seronegative for human immunodeficiency virus antibody (i.e., intact immune function). Subject has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function defined as: Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 (calculated using the CKD-EPI equation [Levey et al, 2009]). If there is a concern that eGFR calculation is not an accurate reflection of renal function, a 24-hour urine collection for creatinine clearance may be used at the investigator's discretion. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both ≤3 times of upper limit of normal (ULN), unless there is suspected disease in the liver. Total bilirubin <2.0 mg/dL, except in subjects with Gilbert's syndrome. Platelet count ≥50,000/μL and absolute neutrophil count of ≥1000/ μL. Platelet transfusions within 14 days of screening are not allowed except for subjects in B-ALL disease cohort with extensive bone marrow disease burden, in which case adequate bone marrow recovery after prior treatment is required to be documented. C-reactive protein (CRP) <2x ULN; subjects with CRP elevation within 2x ULN, ruling out infectious cause will be required. Left ventricular ejection fraction >45% as assessed by echocardiogram (ECHO) or multiple gated acquisition scan performed within 1 month before starting lymphodepleting chemotherapy. ECHO results performed within 6 months before Screening and at least 28 days after the last cancer treatment may be acceptable if the subject has not received any treatment with cardiotoxicity risks. No clinically significant evidence of pericardial effusion or pleural effusion causing clinical symptoms and needing immediate intervention, based on the investigator's opinion. Any known effusion must be stable without need for drainage within 2 weeks of enrollment. No clinically significant renal/pulmonary comorbidities. Baseline oxygen saturation >92% on room air. Key Exclusion Criteria* Criteria for B-ALL: Burkitt cell (L3 ALL) or mixed-lineage acute leukemia. No active central nervous system (CNS) disease. Subjects with a history of CNS involvement must have a documented CR on at least 2 imaging studies at least 3 months apart (with no masses in parenchyma and no ocular involvement) and a negative cerebrospinal fluid cytology on at least 2 evaluations (one evaluation may be during the Screening Period and the other must be at least 3 months prior). Criteria for NHL: No prior or active CNS disease. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression. Active hemolytic anemia. Criteria for B-ALL and NHL: Subject has had a malignancy, besides the malignancies of inclusion (B-ALL or NHL), that in the investigator's opinion, has a high risk of relapse in the next 2 years. In the case of Richter's transformation, subjects may be enrolled with ongoing chronic lymphocytic leukemia/small lymphocytic lymphoma. Uncontrolled and serious fungal, bacterial, viral, protozoal, or other infection that has not resolved and does require therapeutic anti-microbial medications at least 7 days prior to LD. Subjects with elevated CRP must undergo infectious disease workup and the recommendations discussed with medical monitor to be considered on an individual basis. The CRP must be trending toward the normal range for the laboratory with the exception when it's deemed related to the underlying malignancy. Any form of primary immunodeficiency (e.g., severe combined immunodeficiency disease). Active hepatitis B or hepatitis C confirmed by PCR. Subject positive for inactive hepatitis B is allowed to enroll if on prophylactic treatment. Subject is seropositive for hepatitis B antigen with confirmation. If confirmatory tests are negative, the subject can be enrolled. Subject is seropositive for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, the subject must be tested for the presence of RNA by reverse transcription PCR and be hepatitis C virus-RNA negative. Any known uncontrolled cardiovascular disease at the time of Screening that, in the investigator's opinion, renders the subject ineligible, including but not limited to: Active ventricular or atrial dysrhythmia ≥ Grade 2, bradycardia ≥ Grade 2. Myocardial infarction within 6 months before Screening. Pulmonary embolism, deep vein thrombosis, or any other significant coagulopathy including disseminated intravascular coagulation. History of hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening. In case of hypertensive crisis caused by omission of well-established treatment regimen, transient and promptly stabilized, enrollment must be discussed and agreed upon with sponsor and medical monitor. History of severe immediate hypersensitivity reaction to any of the agents used in this study. Presence of a CNS disorder that, in the opinion of the investigator, renders the subject ineligible for treatment. Abnormal findings during the Screening Period or any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject's safety. History of concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or any other known bone marrow failure syndrome. Active uncontrolled autoimmune disease requiring active immunosuppression at the time of Screening (excluding subjects needing steroids for physiologic replacement). Subject has received stem cell transplant within 90 days before Screening. Subject has active GvHD symptoms. Subject has received systemic biologic agent for treatment of disease under study within 28 days of LD or other systemic anti-cancer therapy within 10 days of LD Note: this criterion does not apply if the subject has clear evidence of disease progression after such an agent has been administered and all AEs have resolved to a Grade 2 or less in severity. This should be discussed with the medical monitor for confirmation. Participation in noninterventional registries or epidemiological studies is not excluded. Radiotherapy within 4 weeks before Screening should be discussed with monitor and determined on a case-by-case basis. Presence of pleural/peritoneal/pericardial catheter, as well as biliary and ureteral stents (does not apply to intravenous lines). Subject has received live vaccine within 4 weeks before Screening. Non-live virus vaccines are not excluded. Subject has received CD19-directed therapy other than autologous CD19-directed CAR T therapy within 90 days of the anticipated start date of LD. Additional criteria apply

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: In each cohort (NHL and B-ALL), up to 6 dose levels will be enrolled and treated sequentially. Within each dose level, up to 6 subjects will be treated with PBCAR0191 using a standard 3 + 3 design. The starting dose of PBCAR0191 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 9 × 10^6 CAR T cells/kg. In the absence of DLTs, the dose will be increased using a fixed dose scheme. Additionally, an expansion cohort is introduced into Phase 1 of the protocol to assess safety, tolerability, and clinical benefit of PBCAR0191 treatment regimens in subjects with aggressive CD19+ r/r B-cell NHLs treated with an autologous CAR T product that failed to achieve durable treatment response.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1<br>PBCAR0191, 3 x 10^5 CAR T cells per kg body weight. In this study, PBCAR0191, allogeneic anti-CD19 CAR T Cells, is used to treat patients with relapsed or refractory (r/r) Non-Hodgkin Lymphoma and r/r B-cell Acute Lymphoblastic Leukemia. Route of Administration: Intravenous infusion. Lymphodepletion Conditioning: Lymphodepletion will be conducted several days prior to PBCAR0191 infusion. A combination of fludarabine and cyclophosphamide will be used for lymphodepletion. | Genetic: PBCAR0191<br>* Single dose of Allogeneic Anti-CD19 CAR T cells will be infused<br>* Other names: Allogeneic Anti-CD19 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion.<br>|
| Experimental: Dose Level 2<br>PBCAR0191, 1 x 10^6 CAR T cells per kg body weight. | Genetic: PBCAR0191<br>* Single dose of Allogeneic Anti-CD19 CAR T cells will be infused<br>* Other names: Allogeneic Anti-CD19 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion.<br>|
| Experimental: Dose Level 3a<br>PBCAR0191, 3 x 10^6 CAR T cells per kg body weight. | Genetic: PBCAR0191<br>* Single dose of Allogeneic Anti-CD19 CAR T cells will be infused<br>* Other names: Allogeneic Anti-CD19 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion.<br>|
| Experimental: Dose Level 4<br>PBCAR0191, 6 x 10^6 CAR T cells per kg body weight as 2 administrations of 3 x 10^6 CAR T cells per kg body weight administered after a single lymphodepletion. | Genetic: PBCAR0191<br>* Single dose of Allogeneic Anti-CD19 CAR T cells will be infused<br>* Other names: Allogeneic Anti-CD19 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion.<br>|
| Experimental: Dose Level 4b<br>PBCAR0191, 500 x 10^6 CAR T cells (flat dose) | Genetic: PBCAR0191<br>* Single dose of Allogeneic Anti-CD19 CAR T cells will be infused<br>* Other names: Allogeneic Anti-CD19 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation | The frequency and type of PBCAR0191-related adverse events (AEs), defined as dose limiting toxicities (DLTs) | Day 0 - Day 28 | 
| Expansion Cohort | Objective response rate (ORR) B-ALL: National Comprehensive Cancer Network (NCCN) 2017 criteria NHL: Lugano criteria | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR): Phase 1 dose escalation only | B-ALL: National Comprehensive Cancer Network (NCCN) 2017 criteria NHL: Lugano criteria | 4 years | 
| Complete response (CR) rate: | B-ALL: National Comprehensive Cancer Network (NCCN) 2017 criteria NHL: Lugano criteria | 4 years | 
| Duration of Response (DoR): | - Defined as the duration (days) from initial response to disease progression or death. | 4 years | 
| Progression-free survival (PFS): | Defined as the duration (days) from Day 0 to disease progression or death. | 4 years | 
| Overall survival (OS): | - Defined as the duration (days) from Day 0 to death. | 4 years | 
| Time to next treatment (TNT): | - Defined as the duration (days) from Day 0 to institution of next systemic therapy. | 4 years | 
| AE reporting: | - Defined as all AEs of clinical significance captured on study and specific reporting of DLTs, treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interests (AESIs), and AEs related to study treatment. | 4 years |