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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03666000




Registration number
NCT03666000
Ethics application status
Date submitted
20/08/2018
Date registered
11/09/2018

Titles & IDs
Public title
Dose-escalation, Dose-expansion Study of Safety of Azer-cel (PBCAR0191) in Patients With r/r NHL and r/r B-cell ALL
Scientific 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)
Secondary ID [1] 0 0
PBCAR0191-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Hodgkin Lymphoma 0 0
B-cell Acute Lymphoblastic Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Azer-cel
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - IL-2
Treatment: Drugs - Bendamustine

Experimental: Dose Level 1 - Azer-cel 3 x 10\^5 CAR T cells per kilogram (kg) body weight.

Route of Administration: Intravenous infusion.

Experimental: Dose Level 2 - Azer-cel, 1 x 10\^6 CAR T cells per kg body weight

Experimental: Dose Level 3a - Azer-cel, 3 x 10\^6 CAR T cells per kg body weight.

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.

Experimental: Dose Level 4b - Azer-cel, 500 x 10\^6 CAR T cells (flat dose)

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.


Treatment: Other: Azer-cel
Infusion of Allogeneic Anti-CD19 CAR T cells

Treatment: Drugs: Fludarabine
Specified dose on specified days

Treatment: Drugs: Cyclophosphamide
Specified dose on specified days

Treatment: Drugs: IL-2
Specified dose on specified days

Treatment: Drugs: Bendamustine
Specified dose on specified days
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1 Dose Escalation/Phase 1b Dose Expansion: Frequency of Participants with Azer-cel related Adverse Events (AEs) defined as dose limiting toxicities (DLTs)
Timepoint [1] 0 0
Up to day 720
Primary outcome [2] 0 0
Phase 1b Dose Expansion: Objective response rate (ORR): Dose expansion only
Timepoint [2] 0 0
Up to day 720
Secondary outcome [1] 0 0
Objective Response Rate (ORR): Dose escalation only
Timepoint [1] 0 0
Up to day 720
Secondary outcome [2] 0 0
Complete response (CR) rate
Timepoint [2] 0 0
Up to day 720
Secondary outcome [3] 0 0
Duration of Response (DoR)
Timepoint [3] 0 0
Up to day 720
Secondary outcome [4] 0 0
Progression-free survival (PFS)
Timepoint [4] 0 0
Up to day 720
Secondary outcome [5] 0 0
Overall survival (OS)
Timepoint [5] 0 0
Up to day 720
Secondary outcome [6] 0 0
Time to next treatment (TNT)
Timepoint [6] 0 0
Up to day 720
Secondary outcome [7] 0 0
Number of Participants with AEs
Timepoint [7] 0 0
Up to day 720

Eligibility
Key inclusion criteria
Key Inclusion Criteria

Criteria for B-ALL:

* 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.

Criteria for NHL:

* 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:
* For Phase 1 Dose Escalation:

* 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 1b Dose Expansion:

* 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.

Criteria for both B-ALL and NHL:

* 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:

1. 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.
2. 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.
3. Total bilirubin <2.0 mg/dL, except in participants with Gilbert's syndrome.
4. 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.
5. 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.
6. 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.
7. No clinically significant renal/pulmonary comorbidities.
8. Baseline oxygen saturation >92% on room air.

Key
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 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:

1. Active ventricular or atrial dysrhythmia = Grade 2, bradycardia = Grade 2.
2. Myocardial infarction within 6 months before Screening.
3. 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.

Additional criteria apply

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
11/03/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2027
Actual
Sample size
Target
129
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 0 0
Liverpool Hospital - Liverpool
Recruitment hospital [3] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Maryland
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
Minnesota
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Ohio
Country [12] 0 0
United States of America
State/province [12] 0 0
Rhode Island
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas
Country [14] 0 0
United States of America
State/province [14] 0 0
Wisconsin

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Imugene Limited
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
John Byon, MD, PhD
Address 0 0
Imugene Limited
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Imugene Clinical Team
Address 0 0
Country 0 0
Phone 0 0
984-245-0082
Fax 0 0
Email 0 0
info@imugene.com
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03666000