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Official Title

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)

Phase
Phase 1
Sponsor
Imugene Limited
Enrollment
129
Timeline
Mar 2019 → Jun 2027
About This Study

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.

Eligibility Criteria

Inclusion Criteria

  • 1Criteria for B-ALL:
  • 2Participant has unequivocal r/r CD19+ B-ALL that has been confirmed by morphology, flow cytometry, or a validated minimal residual disease (MRD) assay.
  • 3Participants with Philadelphia chromosome positive disease can be eligible if they are intolerant to tyrosine kinase inhibitor therapy or if they have r/r disease.
  • 4Criteria for NHL:
  • 5Participant 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:
  • 6For Phase 1 Dose Escalation:
  • 7Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation
  • 8FL including Grade 3 or transformed FL
  • 9High-grade B-cell lymphoma
  • 10Primary mediastinal lymphoma
  • 11For Phase 1b Dose Expansion:
  • 12DLBCL not otherwise specified (NOS)
  • 13High grade B-Cell Lymphoma
  • 14DLBCL transformed from the following indolent lymphoma subtypes (Follicular lymphoma, Marginal Zone lymphoma and Waldenstrom's Macroglobulinemia)
  • 15Participant has measurable or detectable (for example positron emission tomography-positive) disease according to the Lugano Classification.
  • 16Participant 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.
  • 17Participant has received no more than 7 systemic lines of anti-cancer therapy for the disease under study.
  • 18Participants 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.
  • 19Expansion 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.
  • 20Criteria for both B-ALL and NHL:
  • 21Eastern Cooperative Oncology Group performance status score of 0 or 1.
  • 22An estimated life expectancy of at least 12 weeks according to the investigator's judgment.
  • 23Seronegative for human immunodeficiency virus antibody (i.e., intact immune function).
  • 24Participant has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function defined as:
  • 25Estimated 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.
  • 26Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both ≤3 times of upper limit of normal (ULN), unless there is suspected disease in the liver.
  • 27Total bilirubin \<2.0 mg/dL, except in participants with Gilbert's syndrome.
  • 28Platelet 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.
  • 29Left 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.
  • 30No 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.
  • 31No clinically significant renal/pulmonary comorbidities.
  • 32Baseline oxygen saturation \>92% on room air.

Exclusion Criteria

  • 1Criteria for B-ALL:
  • 2Burkitt cell (L3 ALL) or mixed-lineage acute leukemia.
  • 3Criteria for NHL:
  • 4Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
  • 5Active hemolytic anemia.
  • 6Criteria for B-ALL and NHL:
  • 7No 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.
  • 8History of another primary malignancy that has not been in remission for at least 2 years with the following exceptions:
  • 9Curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the breast or cervix
  • 10Low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time
  • 11Completely resected Stage 1 solid tumor with low risk for recurrence within 2 years
  • 12In the case of Richter's transformation, participants may be enrolled with ongoing chronic lymphocytic leukemia/small lymphocytic lymphoma.
  • 13Any form of primary immunodeficiency (e.g., severe combined immunodeficiency disease).
  • 14History of hepatitis B or hepatitis C currently receiving ongoing antiviral therapy.
  • 15Any known uncontrolled cardiovascular disease at the time of Screening that, in the investigator's opinion, renders the participant ineligible, including but not limited to:
  • 16Active ventricular or atrial dysrhythmia ≥ Grade 2, bradycardia ≥ Grade 2.
  • 17Myocardial infarction within 6 months before Screening.
  • 18Pulmonary embolism, deep vein thrombosis, or any other significant coagulopathy including disseminated intravascular coagulation.
  • 19History 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.
  • 20History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • 21Presence of a CNS disorder that, in the opinion of the investigator, renders the participant ineligible for treatment.
  • 22Abnormal 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.
  • 23History of concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or any other known bone marrow failure syndrome.
  • 24Active uncontrolled autoimmune disease requiring active immunosuppression at the time of Screening (excluding participants needing steroids for physiologic replacement).
  • 25Participant has received stem cell transplant within 90 days before Screening.
  • 26Participant has active GvHD symptoms.
  • 27Participant 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
  • 28Radiotherapy within 4 weeks before Screening should be discussed with monitor and determined on a case-by-case basis.
  • 29Presence of pleural/peritoneal/pericardial catheter, as well as permeant biliary and ureteral stents (does not apply to intravenous lines).
  • 30Participant has received live vaccine within 4 weeks before Screening. Non-live virus vaccines are not excluded.
  • 31Participant has received CD19-directed therapy other than autologous CD19-directed CAR T therapy within 90 days of the anticipated start date of LD.
  • 32Additional criteria apply

Locations

22 sites participating in this study

Winship Cancer Institute Emory University

Atlanta, Georgia 30322

Recruiting

Edmund Waller, MD

Banner MD Anderson Cancer Center

Gilbert, Arizona 85234

Recruiting

Rajneesh Nath, MD

City of Hope

Duarte, California 91010

Recruiting

Alex Herrera, MD

Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →