Share

Save

Dose-escalation, Dose-expansion Study of Safety of Azer-cel (PBCAR0191) in Patients With r/r NHL and r/r B-cell ALL

PHASE1RECRUITING

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 and r/r B-cell NHL.

info
Simpliy with AI

Study details:

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) and non-Hodgkin lymphoma (NHL). 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.

All participants will be monitored through D720 or progression. All participants who receive a dose of azer-cel will be followed in a separate long-term follow-up (LTFU) study for up to 15 years after exiting this study.

info
Simplify with AI

Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • Participant has unequivocal r/r CD19+ B-ALL that has been confirmed by morphology, flow cytometry, or a validated minimal residual disease (MRD) assay.
  • Participants with Philadelphia chromosome positive disease can be eligible if they are intolerant to tyrosine kinase inhibitor therapy or if they have r/r disease.
  • Participant has unequivocal aggressive CD19+ r/r B-cell NHL that is confirmed by archived tumor biopsy tissue from last relapse after CD19-directed therapy and corresponding pathology report. Alternatively, if at least 1 tumor involved site is accessible at time of Screening, the participant's diagnosis is confirmed by pretreatment biopsy (excisional when possible) or by flow cytometry of fine needle aspirate (FNA). If a participant never had a CR, a sample from the most recent biopsy is acceptable. NHL subtypes included but are not limited to: Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation, FL including Grade 3 or transformed FL, High-grade B-cell lymphoma, Primary mediastinal lymphoma.
  • For Phase 1 Dose Escalation: DLBCL not otherwise specified (NOS), High grade B-Cell Lymphoma, DLBCL transformed from the following indolent lymphoma subtypes (Follicular lymphoma, Marginal Zone lymphoma and Waldenstrom's Macroglobulinemia).
  • Participant has measurable or detectable (for example positron emission tomography-positive) disease according to the Lugano Classification.
  • Participant must have received at least 2 lines of prior anti-cancer therapy for the disease under study, including at least 1 chemoimmunotherapy regimen (e.g., anti-CD20 monoclonal antibody plus chemotherapy), consistent with standard of care treatment guidance (e.g., National Comprehensive Cancer Network [NCCN]), unless no second line therapy of known benefit exists for a given subject. For Richter's transformation, only 1 prior line of therapy is required for the DLBCL component.
  • Participant has received no more than 7 systemic lines of anti-cancer therapy for the disease under study.
  • 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.
  • Expansion 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.
  • 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 (i.e., intact immune function).
  • Participant 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]). For participants receiving an LD regimen that contains 4 days of Fludarabine, an eGFR >=60 mL/min/1.73 m2 (calculated using the CKD-EPI equation) is required. 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 participants 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 participants 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. NHL participants with a platelet count <50,000/μL and absolute neutrophil count (ANC) of <1000/ μL may be enrolled with Medical Monitor approval if there is documentation of significant bone marrow involvement by disease and in the Investigator's assessment, no other reasonable etiology for the low counts. 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 participant 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.
  • Exclusion criteria

  • Burkitt cell (L3 ALL) or mixed-lineage acute leukemia.
  • Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
  • Active hemolytic anemia.
  • No active central nervous system (CNS) disease. Subjects with a prior history of CNS involvement that has been adequately treated ≥3 months prior to study consent and without symptoms or clinical suspicion of relapsed CNS disease may be enrolled.
  • History of another primary malignancy that has not been in remission for at least 2 years with the following exceptions: Curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the breast or cervix, Low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time, Completely resected Stage 1 solid tumor with low risk for recurrence within 2 years, In the case of Richter's transformation, participants may be enrolled with ongoing chronic lymphocytic leukemia/small lymphocytic lymphoma.
  • Any form of primary immunodeficiency (e.g., 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, including but not limited to: Active ventricular or atrial dysrhythmia ≥ Grade 2, bradycardia ≥ Grade 2. Myocardial infarction within 6 months before Screening. Pulmonary embolism, deep vein thrombosis, or any other significant coagulopathy including disseminated intravascular coagulation.
  • History of hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening. In case of hypertensive crisis caused by omission of well-established treatment regimen, transient and promptly stabilized, enrollment must be discussed and agreed upon with sponsor and medical monitor.
  • 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.
  • Abnormal findings during the Screening Period or any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the participant's safety.
  • 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 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. Note: This criterion does not apply if the subject has clear evidence of disease progression after such an agent has been administered and all AEs have resolved to a Grade 2 or less in severity. This should be discussed with the Medical Monitor for confirmation.
  • Radiotherapy within 4 weeks before Screening should be discussed with monitor and determined on a case-by-case basis.
  • 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. 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.
  • info
    Simplify with AI

    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2019-03-11

    Primary completion: 2025-06-01

    Study completion finish: 2027-06-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE1

    trial

    Trial ID

    NCT03666000

    Intervention or treatment

    BIOLOGICAL: Azer-cel

    DRUG: Fludarabine

    DRUG: Cyclophosphamide

    DRUG: IL-2

    DRUG: Bendamustine

    Conditions

    • Non-Hodgkin Lymphoma
    • B-cell Acute Lymphoblastic Leukemia
    Image related to Non-Hodgkin Lymphoma
    • Condition: Non-Hodgkin Lymphoma, B-cell Acute Lymphoblastic Leukemia

    • BIOLOGICAL: Azer-cel and other drugs

    • Camperdown, New South Wales, Australia and more

    • Sponsor: Imugene Limited

    Find a site

    Closest Location:

    Royal Prince Alfred Hospital

    Research sites nearby

    Select from list below to view details:

    • Royal Prince Alfred Hospital

      Camperdown, New South Wales, Australia

    • Liverpool Hospital

      Liverpool, New South Wales, Australia

    • Royal Adelaide Hospital

      Adelaide, South Australia, Australia

    Loading...

    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Dose Level 1
    • Azer-cel 3 x 10\^5 CAR T cells per kilogram (kg) body weight.
    • Route of Administration: Intravenous infusion.
    BIOLOGICAL: Azer-cel
    • Infusion of Allogeneic Anti-CD19 CAR T cells
    EXPERIMENTAL: Dose Level 2
    • Azer-cel, 1 x 10\^6 CAR T cells per kg body weight
    BIOLOGICAL: Azer-cel
    • Infusion of Allogeneic Anti-CD19 CAR T cells
    EXPERIMENTAL: Dose Level 3a
    • Azer-cel, 3 x 10\^6 CAR T cells per kg body weight.
    BIOLOGICAL: Azer-cel
    • Infusion of Allogeneic Anti-CD19 CAR T cells
    EXPERIMENTAL: Dose Level 4
    • 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.
    BIOLOGICAL: Azer-cel
    • Infusion of Allogeneic Anti-CD19 CAR T cells
    EXPERIMENTAL: Dose Level 4b
    • Azer-cel, 500 x 10\^6 CAR T cells (flat dose)
    BIOLOGICAL: Azer-cel
    • Infusion of Allogeneic Anti-CD19 CAR T cells
    EXPERIMENTAL: Dose level 4c
    • 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.
    BIOLOGICAL: Azer-cel
    • Infusion of Allogeneic Anti-CD19 CAR T cells

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Phase 1 Dose Escalation/Phase 1b Dose Expansion: Frequency of Participants with Azer-cel related Adverse Events (AEs) defined as dose limiting toxicities (DLTs)Not SpecifiedUp to day 720
    Phase 1b Dose Expansion: Objective response rate (ORR): Dose expansion only- NHL: Lugano criteriaUp to day 720

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Objective Response Rate (ORR): Dose escalation only* B-ALL: National Comprehensive Cancer Network (NCCN) 2017 criteria * NHL: Lugano criteriaUp to day 720
    Complete response (CR) rate* B-ALL: National Comprehensive Cancer Network (NCCN) 2017 criteria * NHL: Lugano criteriaUp to day 720
    Duration of Response (DoR)- Defined as the duration (days) from initial response to disease progression or death.Up to day 720
    Progression-free survival (PFS)- Defined as the duration (days) from Day 0 to disease progression or death.Up to day 720
    Overall survival (OS)- Defined as the duration (days) from Day 0 to death.Up to day 720
    Time to next treatment (TNT)- Defined as the duration (days) from Day 0 to institution of next systemic therapy.Up to day 720
    Number of Participants with AEs- 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.Up to day 720

    Frequently Asked Questions

    Please note: some questions and answers are submitted by anonymous patients or using AI, and have not been verified by Clinrol

    No questions submitted. Be the first to ask a question!

    You may be eligible to participate in this trial based on your search.Apply for study
    Are you running this trial? If you're a clinic or sponsor, you can claim this study.Claim this trial

    References

    Clinical Trials Gov: Dose-escalation, Dose-expansion Study of Safety of Azer-cel (PBCAR0191) in Patients With r/r NHL and r/r B-cell ALL

    Other trails to consider

    Top searched conditions