Dose-escalation and Dose-expansion Study of Safety of Azer-cel (PBCAR0191) in Participants With Relapsed/Refractory (r/r) Non-Hodgkin Lymphoma (NHL) and r/r B-cell Acute Lymphoblastic Leukemia (B-ALL)

Imugene

Status and phase: Enrolling; Phase 1

Conditions: Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia; B-cell Acute Lymphoblastic Leukemia; Non-Hodgkin Lymphoma

Treatments: Biological: Azer-cel; Drug: Fludarabine; Drug: IL-2; Drug: Cyclophosphamide

Study type: Interventional

Funder types: Industry

Identifiers

NCT03666000

PBCAR0191-01

Details and patient eligibility

About

This is a Phase 1/1b, nonrandomized, open-label, parallel assignment, dose-escalation, and dose-expansion study to evaluate the safety and clinical activity of azer-cel, an allogeneic anti-CD19 CAR T, in adults with r/r B ALL, r/r B-cell NHL and CLL/SLL.

Full description

This is a multicenter, nonrandomized, open-label, parallel assignment, 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 azer-cel in participants with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Before initiating azer-cel, participants will be administered lymphodepletion (LD). At Day 0 of the Treatment Period, participants will receive an intravenous (IV) infusion of azer-cel potentially followed by interleukin-2 (IL-2). All participants will be monitored through D720 or progression. All participants who receive a dose of azer-cel will be asked to consent to a separate long-term follow-up (LTFU) study for up to 15 years after exiting this study.

Enrollment: 135 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria

Criteria for B-ALL:

• Participant has confirmed unequivocal r/r CD19+ B-ALL.

Criteria for NHL and CLL/SLL:

• Participant has unequivocal aggressive CD19+ r/r B-cell NHL that is confirmed by tumor biopsy tissue from last relapse after CD19-directed therapy.

For Phase 1 Dose Escalation:

• Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation
• Follicular lymphoma (FL) including Grade 3 or transformed FL
• High-grade B-cell lymphoma (HGBCL)
• Primary mediastinal lymphoma

For Phase 1b Dose Expansion (CAR T-relapsed cohort):

• DLBCL not otherwise specified (NOS)
• HGBCL
• DLBCL transformed from the following indolent lymphoma subtypes (FL, Marginal Zone lymphoma [MZL], and Waldenstrom's Macroglobulinemia [WM])
• Other large B-cell lymphoma (LBCL) subtypes may be enrolled with approval from the Medical Monitor.
• Participants 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.
• For the expansion CAR T-relapsed cohort only: Participants must have received autologous CD19-directed CAR T therapy and demonstrated clinical response to the treatment at Day 28 or later, followed by relapse or progression.

For Phase 1b dose expansion (CAR T-naive cohort):

• DLBCL NOS
• DLBCL transformed from the following indolent lymphoma subtypes (FL, MZL, and WM)
• HGBCL
• FL (Grade 1-3a)
• MZL that is fluorodeoxyglucose (FDG)-avid on positron emission tomography (PET) scan
• WM
• CLL/SLL
• Primary central nervous system (CNS) lymphoma (PCNSL)
• Other LBCL subtypes may be enrolled with approval from the Medical Monitor.
• Participant must have received at least 1-2 prior lines of therapy, depending on histological subtype but no more than 7 systemic lines of anti-cancer therapy.

Criteria for both B-ALL, NHL, and CLL/SLL:

• 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.
• Participant has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function.

Key Exclusion Criteria

Criteria for B-ALL:

• Burkitt cell (L3 ALL) or mixed-lineage acute leukemia.

Criteria for NHL:

• 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:

• No active CNS disease, excluding PCNSL
• History of another primary malignancy
• Any form of primary immunodeficiency (for example, severe combined immunodeficiency disease).
• History of hepatitis B or hepatitis C currently receiving ongoing antiviral therapy.

Any known uncontrolled cardiovascular disease at the time of Screening that, in the investigator's opinion, renders the participant ineligible

• History of hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening.
• 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 participant ineligible for treatment.
• 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 participants needing steroids for physiologic replacement).
• Participant has received stem cell transplant within 90 days before Screening.
• Participant has active graft-versus-host disease (GvHD) symptoms.
• Participant has received a systemic biologic agent for treatment of the disease under study within 28 days of LD, other systemic anti-cancer therapy within 10 days or 5 half-lives (whichever is shorter) of LD, and no pulse steroid for disease control within 3 days of LD.
• Radiotherapy within 4 weeks before Screening.
• Presence of pleural/peritoneal/pericardial catheter, as well as permeant biliary and ureteral stents (does not apply to intravenous lines).
• Participant has received live vaccine within 4 weeks before Screening. Note: Non-live virus vaccines are not excluded.
• Participant 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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135 participants in 6 patient groups

Phase 1 Dose Escalation: Azer-cel Dose Level 1

Experimental group

Description:

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

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Biological: Azer-cel

Phase 1 Dose Escalation: Azer-cel Dose Level 2

Experimental group

Description:

Azer-cel, 1 x 10\^6 CAR T cells per kg body weight. Route of Administration: Intravenous infusion

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Biological: Azer-cel

Phase 1 Dose Escalation: Azer-cel Dose Level 3a

Experimental group

Description:

Azer-cel, 3 x 10\^6 CAR T cells per kg body weight. Route of Administration: Intravenous infusion

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Biological: Azer-cel

Phase 1 Dose Escalation: Azer-cel Dose Level 4

Experimental group

Description:

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 on Day 0 and Day 10. Route of Administration: Intravenous infusion

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Biological: Azer-cel

Phase 1 Dose Escalation: Azer-cel Dose Level 4b

Experimental group

Description:

Azer-cel, 500 x 10\^6 CAR T cells (flat dose). Route of Administration: Intravenous infusion

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Biological: Azer-cel

Phase 1B Dose Expansion: Azer-cel

Experimental group

Description:

Azer-cel will be administered at a dose level established in Phase 1. Route of Administration: Intravenous infusion

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Biological: Azer-cel

Drug: IL-2