CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.

主要终点：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 · ORR for participants with B-ALL will be assessed by National Comprehensive Cancer Network (NCCN) 2017 criteria. · Up to Day 720；Phase 1b Dose Expansion: ORR NHL · 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. · Up to Day 720
次要终点：Phase 1 Dose Escalation: ORR；Complete Response (CR) Rate；Duration of Response (DoR)；Progression-free survival (PFS)；Overall survival (OS)；Time to next treatment (TNT)；Number of Participants with AEs

• Phase 1 Dose Escalation: Azer-cel Dose Level 1 · EXPERIMENTAL · Azer-cel, 3 x 10\^5 CAR T cells per kilogram (kg) body weight. Route of Administration: Intravenous infusion
• Phase 1 Dose Escalation: Azer-cel Dose Level 2 · EXPERIMENTAL · Azer-cel, 1 x 10\^6 CAR T cells per kg body weight. Route of Administration: Intravenous infusion
• Phase 1 Dose Escalation: Azer-cel Dose Level 3a · EXPERIMENTAL · Azer-cel, 3 x 10\^6 CAR T cells per kg body weight. Route of Administration: Intravenous infusion
• Phase 1 Dose Escalation: Azer-cel Dose Level 4 · EXPERIMENTAL · 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
• Phase 1 Dose Escalation: Azer-cel Dose Level 4b · EXPERIMENTAL · Azer-cel, 500 x 10\^6 CAR T cells (flat dose). Route of Administration: Intravenous infusion
• Phase 1B Dose Expansion: Azer-cel · EXPERIMENTAL · Azer-cel will be administered at a dose level established in Phase 1. Route of Administration: Intravenous infusion
• Phase 1B Dose Expansion: Azer-cel + Bruton's tyrosine kinase inhibitor · EXPERIMENTAL · Azer-cel will be administered at a dose level established in Phase 1. Route of Administration: Intravenous infusion In combination with a Bruton's tyrosine kinase inhibitor

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.