B-cell Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, Small Lymphocytic Lymphoma
Conditions
Brief summary
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.
Detailed 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.
Interventions
BIOLOGICALAzer-cel
Infusion of Allogeneic Anti-CD19 CAR T cells
DRUGFludarabine
Specified dose on specified days
DRUGCyclophosphamide
Specified dose on specified days
DRUGIL-2
Specified dose on specified days
DRUGIbrutinib, Acalabrutinib, Zanubrutinib, or Pirtobrutinib
Specified dose on specified days
Sponsors
Imugene Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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 and Con-BTKi cohort): For indication with an approved autologous CAR T-cell therapy, participants must be ineligible for or unable to access autologous CAR T-cell therapy. * 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. Participants enrolling into the Con-BTKi cohort must: * Be receiving a BTKi (as a monotherapy or combination therapy) as the last, systemic anti-cancer regimen before study entry. Alternatively, if previously refractory to one or more BTK inhibitor(s) and the last systemic anti-cancer therapy before study entry did not include a BTKi, one of the previous BTK inhibitors may be used. * Have radiologic or clinical disease progression while on the BTKi * Agree to remain on BTKi therapy during the protocol-defined BTKi treatment window * Have been tolerant to BTKi 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Dose Escalation/Phase 1b Dose Expansion: Number of Participants with Azer-cel-related AEs Defined as Dose-limiting Toxicities (DLTs) | Up to Day 720 | — |
| Phase 1b Dose Expansion: Objective Response Rate (ORR) B-ALL | Up to Day 720 | ORR for participants with B-ALL will be assessed by National Comprehensive Cancer Network (NCCN) 2017 criteria. |
| Phase 1b Dose Expansion: ORR NHL | Up to Day 720 | ORR for participants with NHL will be assessed by Lugano classification, International Workgroup on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines, International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) criteria, and International Workshop on Waldenstrom's Macroglobulinemia (IWWM)-11 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with AEs | Up to day 720 | \- 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. |
| Phase 1 Dose Escalation: ORR | Up to Day 720 | * B-ALL: NCCN 2017 criteria * NHL: Lugano classification |
| Complete Response (CR) Rate | Up to day 720 | * B-ALL: NCCN 2017 criteria * NHL: Lugano classification |
| Progression-free survival (PFS) | Up to day 720 | \- Defined as the duration (days) from Day 0 to disease progression or death. |
| Duration of Response (DoR) | Up to day 720 | \- Defined as the duration (days) from initial response to disease progression or death. |
| Overall survival (OS) | Up to day 720 | \- Defined as the duration (days) from Day 0 to death. |
| Time to next treatment (TNT) | Up to day 720 | \- Defined as the duration (days) from Day 0 to institution of next systemic therapy. |
Countries
Australia, United States
Contacts
CONTACTImugene Clinical Team
STUDY_CHAIRJohn Byon, MD, PhD
Imugene Limited
Outcome results
None listed