What side effects are associated with this type of intervention?

Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19, such as the treatment being studied in the PBCAR0191 trial for Non-Hodgkin's Lymphoma, is associated with several significant side effects. These include cytokine release syndrome (CRS), which can cause fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing. Neurotoxicity is another serious side effect, leading to confusion, seizures, and severe headaches. Additionally, patients may experience cytopenias (low blood cell counts), infections, and fatigue. These side effects necessitate careful monitoring and management.

What prior FDA approvals exist?

The FDA has approved several CAR-T cell therapies for the treatment of Non-Hodgkin's Lymphoma, particularly those targeting CD19. Notable approvals include axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah), both of which are used for relapsed or refractory large B-cell lymphoma, a subtype of NHL. These therapies involve modifying a patient's T-cells to express a receptor that targets the CD19 antigen on B-cells, similar to the approach being studied in the PBCAR0191 trial.

What other types of research exist?

Promising, novel alternatives to PBCAR0191 for Non-Hodgkin's Lymphoma patients include: 1) Tisagenlecleucel (Kymriah), a CD19-directed CAR T-cell therapy approved for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). 2) Pembrolizumab, an immune checkpoint inhibitor that has shown efficacy in various cancers and is being investigated for use in NHL. 3) Acalabrutinib, a Bruton tyrosine kinase (BTK) inhibitor, which is used in combination with other therapies for B-cell malignancies. These alternatives offer different mechanisms of action and have demonstrated clinical benefits in treating NHL.

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CAR T-cell Therapy

PBCAR0191 for Blood Cancer

Phase 1

Recruiting

Research Sponsored by Imugene Limited

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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.

Subject has unequivocal r/r CD19+ B-ALL that has been confirmed by morphology, flow cytometry, or a validated minimal residual disease assay.

Must not have

Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.

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).

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to day 720

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a new therapy using specially altered immune cells in adults with certain types of blood cancers that have not responded to other treatments. The goal is to find a safe and effective amount.

Who is the study for?

Adults with aggressive CD19+ B-cell Non-Hodgkin's Lymphoma (NHL) or relapsed/refractory B-cell Acute Lymphoblastic Leukemia (ALL), who have tried at least two prior treatments, can join this trial. They should not have severe heart, lung, kidney, liver issues or active infections and must be HIV negative. Those with a history of CNS disease need to show clear recovery.

What is being tested?

The study is testing PBCAR0191 in combination with Fludarabine and Cyclophosphamide for safety and effectiveness in treating NHL and ALL. It involves gradually increasing the dose to find the best balance between benefits and side effects.

What are the potential side effects?

Potential side effects may include reactions related to immune system activation such as fever, fatigue, nausea; blood cell count changes leading to increased infection risk; organ inflammation; plus specific risks from chemotherapy like hair loss and mouth sores.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My leukemia (B-ALL) is resistant or has returned and tests confirm it targets CD19.

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I've had no more than 2 treatments after my CAR T-cell therapy.

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I had CAR T therapy for cancer, responded well initially, but then my cancer came back.

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My aggressive B-cell NHL is confirmed to be CD19 positive from my last relapse.

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I do not have serious kidney or lung conditions.

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My disease can be measured or seen on scans.

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I am fully active or restricted in physically strenuous activity but can do light work.

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I have had 7 or fewer treatments for my cancer.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I need urgent treatment because my tumor is causing blockages or pressing on blood vessels.

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I do not have active brain or spinal cord disease, and tests confirm this.

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I have a condition that significantly weakens my immune system.

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I do not have serious heart rhythm problems.

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I have a history of blood clots or significant bleeding disorders.

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I have a genetic condition like Fanconi anemia affecting my bone marrow.

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I do not have an active autoimmune disease needing strong medication now.

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I have an active condition where my red blood cells are being destroyed faster than they can be made.

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My leukemia is either Burkitt (L3 ALL) or mixed-lineage.

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I have never had, nor do I currently have, any brain or spinal cord diseases.

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I am experiencing symptoms of graft-versus-host disease.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to day 720

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to day 720

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to day 720 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Phase 1b Dose Expansion: Objective response rate (ORR): Dose expansion only

Secondary study objectives

Complete response (CR) rate

Duration of Response (DoR)

Number of Participants with AEs

+4 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

6Treatment groups

Experimental Treatment

Group I: Dose level 4cExperimental Treatment3 Interventions

Azer-cel, 1000 x 10\^6 CAR T cells (flat dose) given as 2 administrations of 500 × 106 cells/per dose on Day 0 and Day 5.

Group II: Dose Level 4bExperimental Treatment5 Interventions

Azer-cel, 500 x 10\^6 CAR T cells (flat dose)

Group III: Dose Level 4Experimental Treatment3 Interventions

Azer-cel, 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.

Group IV: Dose Level 3aExperimental Treatment3 Interventions

Azer-cel, 3 x 10\^6 CAR T cells per kg body weight.

Group V: Dose Level 2Experimental Treatment3 Interventions

Azer-cel, 1 x 10\^6 CAR T cells per kg body weight

Group VI: Dose Level 1Experimental Treatment3 Interventions

Azer-cel 3 x 10\^5 CAR T cells per kilogram (kg) body weight. Route of Administration: Intravenous infusion.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

IL-2

2007

Completed Phase 4

~1100

Bendamustine

2015

Completed Phase 3

~3230

Fludarabine

2012

Completed Phase 4

~1860

Cyclophosphamide

2010

Completed Phase 4

~2310

0 / 20Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Non-Hodgkin's Lymphoma (NHL) treatments include chemotherapy, monoclonal antibodies, and Chimeric Antigen Receptor (CAR) T-cell therapy. CAR T-cell therapy, such as PBCAR0191, involves modifying a patient's T-cells to express a receptor specific to the CD19 antigen found on B-cells. These engineered T-cells are then infused back into the patient, where they seek out and destroy CD19-positive cancer cells. This targeted approach is significant for NHL patients as it offers a personalized treatment option that can lead to durable remissions, especially in relapsed or refractory cases where traditional therapies may have failed.