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)

Официальное название

A Phase 1/1b, Open-label, Dose-escalation, Dose-expansion, Parallel Assignment Study to Evaluate Safety and Clinical Activity of PBCAR0191 (Azercabtagene Zapreleucel or "Azer-cel") in Subjects With Relapsed/Refractory (r/r) Non-Hodgkin Lymphoma (NHL) and r/r B-cell Acute Lymphoblastic Leukemia (B-ALL)

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат Azer-cel
  Infusion of Allogeneic Anti-CD19 CAR T cells
• Препарат Fludarabine
  Specified dose on specified days
• Препарат Cyclophosphamide
  Specified dose on specified days
• Препарат IL-2
  Specified dose on specified days

Первичные конечные точки

• Phase 1 Dose Escalation/Phase 1b Dose Expansion: Number of Participants with Azer-cel-related AEs Defined as Dose-limiting Toxicities (DLTs) [Срок оценки: Up to Day 720]
• Phase 1b Dose Expansion: Objective Response Rate (ORR) B-ALL [Срок оценки: Up to Day 720]
• Phase 1b Dose Expansion: ORR NHL [Срок оценки: Up to Day 720]

Вторичные конечные точки (7)

• Phase 1 Dose Escalation: ORR [Срок оценки: Up to Day 720]
• Complete Response (CR) Rate [Срок оценки: Up to day 720]
• Duration of Response (DoR) [Срок оценки: Up to day 720]
• Progression-free survival (PFS) [Срок оценки: Up to day 720]
• Overall survival (OS) [Срок оценки: Up to day 720]
• Time to next treatment (TNT) [Срок оценки: Up to day 720]
• Number of Participants with AEs [Срок оценки: Up to day 720]

Критерии участия

Критерии включения

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.

Критерии исключения

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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 18 центров

• Banner MD Anderson Cancer Center — Gilbert
• City of Hope — Duarte
• H. Lee Moffitt Cancer Center — Tampa
• Winship Cancer Institute Emory University — Atlanta
• Northside Hospital Cancer Institute — Atlanta
• University of Maryland — Baltimore
• Tufts Medical Center — Boston
• Dana-Farber Cancer Institute — Boston
• … и ещё 10 центров

Австралия · 5 центров

• Royal Prince Alfred Hospital — Camperdown
• Liverpool Hospital — Liverpool
• Royal Adelaide Hospital — Adelaide
• St Vincent's Hospital Melbourne — Fitzroy
• Barwon Health - Andrew Love Cancer Centre — Geelong

Идентификаторы

NCT: NCT03666000 · PBCAR0191-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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