Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000673448p
Ethics application status
Not yet submitted
Date submitted
6/05/2025
Date registered
25/06/2025
Date last updated
25/06/2025
Date data sharing statement initially provided
25/06/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Identifying Ultra-High Risk Large B-Cell Lymphoma Patients for Early Treatment with Axicabtagene Ciloleucel: A therapeutic arm of the ALLG NHL34 CLARIFY Study
Scientific title
Detection of Ultra-High Risk Large B-Cell Lymphoma for Early
Delivery of Axicabtagene Ciloleucel: A therapeutic arm of the
ALLG NHL34 CLARIFY study
Secondary ID [1] 314311 0
ALLG NHL34/DA
Universal Trial Number (UTN)
Trial acronym
Linked study record
This is an investigational combination treatment arm within the ALLG NHL34 CLARIFY trial platform, which is registered on ANZCTR with ID ACTR12619001656123.

Health condition
Health condition(s) or problem(s) studied:
Ultra-High Risk Large B-Cell Lymphoma 337261 0
Condition category
Condition code
Blood 333663 333663 0 0
Haematological diseases
Cancer 333664 333664 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an investigational combination treatment arm within the ALLG NHL34 CLARIFY trial platform, which is registered on ANZCTR with ID ACTR12619001656123.

This study is for patients with Primary refractory and early relapsed diffuse large B cell lymphoma (DLCBL) who enter the NHL34 Prognostic arm. These patients may then be identified as Ultra High Risk (UHR) Large B-Cell Lymphoma (LBCL). Specifically, it aims to targets patients early on who indicate a suboptimal response to initial treatments and who may benefit from CAR-T cell therapy.

The investigation product is a single Chimeric Antigen Receptor T cells (CAR-T) infusion with Axicabtagene Ciloleucel (Axi-cel) administered intravenously at a target dose of 2x10^6 cells/kg of treatment following lymphodepletion.

A patient is identified and confirmed as Ultra High Risk (UHR) Large B Cell Lymphoma (LBCL) from the NHL34 Prognostic arm by the CLARIFY-Prognostic Reference Committee (CPRC). The patient can be treated with CAR-T infusion with Axi-cel satisfying either a 1) Positron Emission Tomography (PET) or 2) Minimal Residual Disease (MRD) criteria.

Satisfying a PET criteria means there is a suboptimal response at interim cycle 4 of treatment at day 15, defined as:
1) Stable disease, or
2) Partial Metabolic Response of less than 70 percent change in Standardised Uptake Value (SUV) at any lesion, or
3) Partial Metabolic Response demonstrating Deauville V avidity.

A patient may also be identified as UHR by satisfying a MRD criteria: Patients either in complete or partial metabolic response with detectable MRD by PVSeq at end-of-induction on cycle 6 of treatment on day 15 (C6D15).

"Leukapheresis":
Patients will undertake leukapheresis within 21 days of registration. Once a leukapheresis date is planned, patients must enroll in the appropriate Kite portal. The Kite portal is the web-based platform used to manage trials involved in CAR-T cell therapies. The collection of peripheral blood mononuclear cells (PBMCs) will be collected from the patient to obtain T cells for the manufacture of Axicabtagene Ciloleucel (Axi-cel). Leukapheresed cells obtained at participating collection centres will be shipped to the manufacturer’s facility.
-Glucocorticoids must be avoided for 7 days prior to leukapheresis if administered at a pharmacological dose (greater or equal to 5mg/day of prednisone or equivalent doses of other corticosteroids).
-Administration of systemic immunochemotherapy must not be administered a minimum of 14 day prior to leukapheresis.

"Bridging therapy-Optional". At discretion of the investigator.
Bridging therapy is used to prevent disease progression, maintain patient stability, and/or optimize CAR-T effectiveness by reducing cancer burden before CAR-T cell infusion. Administration will be at the discretion of the investigator.
There are two options for bridging therapy: non-chemotherapy and chemotherapy.
The non-chemotherapy option includes:
1) Corticosteroid (max 100mg prednisone or equivalent daily for a maximum 14 days),
2) Rituximab monotherapy (375mg/m2 administered weekly for a maximum of 4 doses),
3) Localized radiation therapy for symptom control may also be allowed alone or in combination with other bridging therapies.

The chemotherapy-based options includes 1) Rituximab at 375 mg/m2, 2) Oxaliplatin at 100mg/m2, and 3) Gemcitabine at 1000mg/m2. All administered via intravenous (IV) infusion on Day 1. A cycle of this bridging chemotherapy typically lasts 14 days but can be adjusted based on an individual circumstances. Patients will receive at least one cycle with up to four cycles permitted if additional time is needed to generate CAR-T cells. Other systemic chemotherapy-containing bridging therapies are not allowed. At the physician's discretion, Rituximab, gemcitabine, and oxaliplatin drug combination can be supplemented with radiotherapy for bulky or symptomatic lesions.

"Lymphodepleting Chemotherapy"
Once availability of Axi-cel is confirmed and there is no indications of the following:
1) Systemic antimicrobials received within 48hr of commencing on day 5
2) Recorded temperatures (over 38 degree Celsius) within 72 hours of commencing on day 5
3) C-reactive protein (CRP) of greater than 100mg/L within 5 days of commencing on day 5
4) Signs or symptoms of new active infection.

Fludarabine at 30 mg/m2 and cyclophosphamide 500 mg/m2 is administered each day for 3 days, followed by 2 rest days through IV infusion. This is to deplete the patient's lymphocytes and create a favorable environment for the infused CAR-T cells.

"CAR-T infusion with Axicabtagene Ciloleucel (Axi-cel)"
CAR-T infusion with Axi-cell will be administered intravenously at a target dose of 2x10^6 cells/kg. Upon administration, the date will be noted as Day 0 and referred to for post-treatment and 24 month follow up purposes. All patients will be monitored daily for 7 days post infusion for signs and symptoms of Cytokine Release Syndrome (CRS) and neurologic events.

All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance. Only Kite accredited sites will be permitted to administer Axi-cel. The product is labelled per local regulations with the patient's unique subject identification number assigned at the time of registration.
Intervention code [1] 330925 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 341260 0
To evaluate the ‘deliverability’ of Axi-cel in UHR-LBCL patients, as identified using the NHL34 CLARIFY-Prognostic Platform. This is defined as the proportion of patients enrolled to the NHL34 CLARIFY-Therapeutic Domain A achieving successful leukapheresis, CAR-T cell generation and infusion of product.
Timepoint [1] 341260 0
1. Day 1-7-Assessments to be completed daily post-infusion, and then at: 2. Day 30 post-infusion 3. Day 60 post-infusion 4. Day 100 post-infusion
Secondary outcome [1] 446927 0
To characterize the safety profile of Axi-cel in UHR-LBCL participants including the rate of SAEs, AESIs, and patient deaths.
Timepoint [1] 446927 0
Incidence of SAEs and AES until 100 days from time of Axicabtagene ciloleucel infusion. Long term follow up of late AESI will be performed 3, 12, and 24 months post end of induction (EOI).
Secondary outcome [2] 446929 0
Minimal Residual Disease (MRD) negativity
Timepoint [2] 446929 0
1. Day 30 post-infusion 2. Day 100 post-infusion 3. 24 months from end of induction (EOI) (measured from date of the Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) used to assign Ultra High Risk (UHR) Large Beta Cell Lymphoma (LBCL) by CLARIFY-Prognostic Reference Committee (CPRC))
Secondary outcome [3] 446931 0
Progression Free Survival (PFS)
Timepoint [3] 446931 0
Progression Free Survival (PFS) will be measured from: 1. Day 0-Time of axicabtagene ciloleucel infusion 2. End of Induction - date of the Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) used to assign Ultra High Risk (UHR) Large Beta Cell Lymphoma (LBCL) by CLARIFY-Prognostic Reference Committee (CPRC).
Secondary outcome [4] 448104 0
Event Free Survival (EFS)
Timepoint [4] 448104 0
Event Free Survival (EFS) will be measured from: 1. Day 0-Time of axicabtagene ciloleucel infusion 2. End of Induction - date of the Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) used to assign Ultra High Risk (UHR) Large Beta Cell Lymphoma (LBCL) by CLARIFY-Prognostic Reference Committee (CPRC)
Secondary outcome [5] 448105 0
Overall Survival (OS)
Timepoint [5] 448105 0
Overall Survival (OS) will be measured from: 1. Day 0-Time of axicabtagene ciloleucel infusion 2. End of Induction - date of the Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) used to assign Ultra High Risk (UHR) Large Beta Cell Lymphoma (LBCL) by CLARIFY-Prognostic Reference Committee (CPRC)
Secondary outcome [6] 448106 0
Lymphoma Specific Survival (LSS)
Timepoint [6] 448106 0
Lymphoma Specific Survival (LSS) will be measured from: 1. Day 0-Time of axicabtagene ciloleucel infusion 2. End of Induction - date of the Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) used to assign Ultra High Risk (UHR) Large Beta Cell Lymphoma (LBCL) by CLARIFY-Prognostic Reference Committee (CPRC)

Eligibility
Key inclusion criteria
1. Enrolled onto the NHL34 CLARIFY-Prognostic Platform (ACTR12619001656123).
2. As part of participation on the NHL34 CLARIFY-Prognostic platform, received centralised fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and Minimal Residual Disease (MRD) circulating tumour DNA (ctDNA) reporting as per protocol, and received 4 to 6 cycles of the curative-intent chemotherapy as proposed at enrolment (allowing for appropriate dose reductions if required).
3. The NHL34 CLARIFY-Prognostic Reference Committee (CPRC) deems the patient to have met Ultra High Risk (UHR) criteria by either PET or MRD criteria:
a. PET Criteria: Interim PET at the 4th cycle of treatment on day 15 (C4D15) demonstrates any of:
I. Stable disease
II. Partial metabolic response with reduction in Standardized Uptake Value (SUV) of less than 70 percent
III. Partial metabolic response with Deauville V
b. MRD Criteria: End of Treatment PET at the sixth cycle of treatment on day 15 (C6D15) demonstrates complete or partial metabolic response with detectable minimal residual disease by Phased-variant ct DNA Sequencing (PVSeq) assay.
4. CD19 positive by immunohistochemistry or flow cytometry on archival tissue biopsy.
5. Adequate bone marrow function defined as:
a. Absolute neutrophil count (ANC) greater or equal to 1.0 x 109/L
b. Platelet count greater or equal to 75 x 109/L
c. Absolute lymphocyte count greater or equal to 100/µL
Adequate function defined as creatinine clearance (as estimated by any local institutional method) greater or equal to 60 mL/minute
6. Adequate hepatic function defined as:
a. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels less or equal to 2.5 × upper limit of normal (ULN) or less or equal 5 x ULN if documented liver involvement of lymphoma.
b. Total bilirubin less or equal 1.5 mg/dL, except in subjects with Gilbert’s Syndrome or documented LBCL liver or pancreatic involvement where less or equal to 3.0 times the ULN
7. Adequate cardiac function defined as:
a. Left ventricular ejection fraction (LVEF) greater or equal to 50%
b. No evidence of clinically significant pericardial effusion.
c. No clinically significant abnormal electrocardiogram (ECG) findings.
8. Adequate pulmonary function defined as:
a. No evidence of Grade 2 (CTCAE 5.0) or greater pleural effusion or ascites (patients with Grade 1 ascites or pleural effusion are eligible).
b. Baseline oxygen saturation greater than 92% on room air.
9. Females of childbearing potential must have a negative serum or urine pregnancy test.
10. ECOG 0-2 at enrollment.
11. Life expectancy of at least over 6 months at the time of screening.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Histological subtypes of Large B Cell Lymphoma (LBCL) including mediastinal grey zone lymphoma; primary mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma; primary large B-cell lymphoma of immune-privileged sites; primary effusion Diffuse Large B Cell lymphoma (DLBCL); primary cutaneous DLBCL, leg type; Post-Transplant Lymphoproliferative Disease
2. Primary or secondary Central Nervous System (CNS) lymphoma at the time of recruitment to the study
a. Other lymphoma therapy with the exception of Corticosteroids (100mg or equivalent for under 14 days)
b. Radiotherapy to target lesions as consolidation is allowed provided intent and anatomical location of consolidative radiotherapy is prespecified prior to or at enrolment. Radiation prior to enrolment is not permitted.
c. CNS Prophylaxis (intrathecal or high-dose methotrexate) may be provided at treating clinician discretion as per local guidelines.
3. Pregnancy or lactation.
4. History of other malignancy that could affect compliance with the protocol or interpretation of results
a. Participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible.
b. Participants with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible.
c. Participants receiving adjuvant endocrine therapy for non-metastatic, hormone receptor greater or equal to positive breast cancer for greater or equal to 2 years prior to enrollment are eligible.
d. Participants with any other malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for greater or equal to 2 years prior to enrolment are eligible.
5. Severe active infection.
6. Has any other clinically important abnormalities as determined by the recruiting investigator that may interfere with participation in or compliance with the study.
7. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent to the trial.
8. Evidence of progressive disease at any point during first-line treatment (1L) immunochemotherapy as evidenced by Deauville score 4 or 5 in any lesion with an increase in intensity of fluorodeoxyglucose (FDG) uptake from baseline and/or new FDG-avid foci consistent with lymphoma.
9. Rapid disease progression during screening/apheresis period that the investigators feel is unlikely to be controlled using permissible bridging options.
10. Acute or chronic active hepatitis B or C or HIV. In the setting of positive history or serology consistent with past exposure, undetectable viral load must be demonstrated by polymerase chain reaction (PCR) and/or nucleic acid testing. Prophylaxis for hepatitis B must have been continued throughout frontline treatment.
11. Since enrolment in the NHL34 CLARIFY-Prognostic Platform, the development and presence of detectable central nervous system (CNS) lymphoma.
12. Presence of a CNS disorder including:
a. Dementia
b. Autoimmune disease with CNS involvement
c. Cerebral oedema with confirmed structural defects by appropriate imaging
d. Seizure disorders requiring active anticonvulsive medication.
e. Any other disorder the registering investigator feels would prohibit inclusion into this domain.
13. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrolment to this treatment domain.
14. History of non-line associated, clinically significant deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of screening.
15. Prior grade 3-4 Cytokine Release Syndrome (CRS) or Immune effector cell–associated Neurotoxicity (ICANS) if prior exposure to T cell redirecting therapies (i.e. frontline bispecific antibodies)
16. Severe active infection requiring ongoing treatment (bacterial, viral, fungal) at the time of screening. Sever Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) infection must be clinically resolved for 14 days prior to registration.
17. Primary immunodeficiency
18. Any medical condition per investigator assessment likely to interfere with assessment of safety or efficacy of study treatment.
19. History of severe immediate hypersensitivity reaction or severe intolerance to any of the agents used in this study, including the lymphodepletion chemotherapy (cyclophosphamide or fludarabine) or CRS management (glucocorticoids, tocilizumab, anakinra).

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
23/10/2025
Actual
Date of last participant enrolment
Anticipated
23/10/2027
Actual
Date of last data collection
Anticipated
23/10/2029
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 318895 0
Other Collaborative groups
Name [1] 318895 0
Australasian Leukaemia and Lymphoma Group
Country [1] 318895 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Country
Australia
Secondary sponsor category [1] 321281 0
None
Name [1] 321281 0
Address [1] 321281 0
Country [1] 321281 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 317449 0
Metro South Human Research Ethics Committee
Ethics committee address [1] 317449 0
Ethics committee country [1] 317449 0
Australia
Date submitted for ethics approval [1] 317449 0
31/07/2025
Approval date [1] 317449 0
Ethics approval number [1] 317449 0

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

Contacts
Principal investigator
Name 141070 0
Dr Joshua Tobin
Address 141070 0
Blood Cancer Research Group, Translational Research Institute, 37 Kent Street Woolloongabba QLD 4102 AUSTRALIA
Country 141070 0
Australia
Phone 141070 0
+61 4 3204 3445
Fax 141070 0
Email 141070 0
[email protected]
Contact person for public queries
Name 141071 0
Delaine Smith
Address 141071 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 141071 0
Australia
Phone 141071 0
+61 03 83739701
Fax 141071 0
Email 141071 0
[email protected]
Contact person for scientific queries
Name 141072 0
Delaine Smith
Address 141072 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 141072 0
Australia
Phone 141072 0
+61 03 83739701
Fax 141072 0
Email 141072 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers

• Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply that the requester must agree to before access is granted.

Conditions for requesting access:
• No requirements
What individual participant data might be shared?
• De-identified IPD data for all data collected during the trial

What types of analyses could be done with individual participant data?
• Any type of analysis
Assessed on a case-by-case basis

When can requests for individual participant data be made (start and end dates)?
From:
Data available 3 months following publication

To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to [email protected]

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocol  [email protected] Access can be requested via the Health Data Austra... [More Details]


Results publications and other study-related documents

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