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Trial registered on ANZCTR


Registration number
ACTRN12619001656123p
Ethics application status
Not yet submitted
Date submitted
15/10/2019
Date registered
27/11/2019
Date last updated
27/11/2019
Date data sharing statement initially provided
27/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to see how feasible it is to deliver Chimeric antigen receptor (CAR) T cells to patients diagnosed early with Primary refractory and early relapsed diffuse large B cell lymphoma.
Scientific title
Clarifying the role of early application of CAR T cells in Primary refractory and early relapsed diffuse large B cell lymphoma patients.
Secondary ID [1] 298640 0
CLARIFY NHL34
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Large B cell Lymphoma 313522 0
Condition category
Condition code
Cancer 311959 311959 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
After completing 4 cycles of R-CHOP chemotherapy, cycles take place every 3 weeks.
A cycle of R-CHOP consists of
Rituximab 375mg/m2 Infusion through a vein on Day 1
Cyclophosphamide 750mg/m2 infusion through a vein on Day 1
Doxorubicin 50mg/m2 Infusion through a vein on Day 1
Vincristine 1.4mg/m2 (2mg max) Infusion through a vein
Prednisolone 100mg/day once a day for 6 days orally with a tablet

Patients will undergo a PET/CT scan if the patient is refractory they will then go on to receive 2 cycles of R-ICE (A cycle of RICE is 21 days) or 2 more cycles of R-CHOP depending on the scan result as reviewed by the physician.
For patients receiving 2 more cycles of R-CHOP they will be assessed at completion of therapy and then every four months with clinical assessment and PET/CT scanning for one year. They will then have a CT neck, chest abdomen and pelvis at 24 months.

A cycle of R-ICE consists of
Rituximab 3752 infusion through the vein on Day 1
Etoposide 100 mg/m2, 20 mins infusion through the vein on Days 1,2 & 3
Carboplatin max 800 mg, 1hr infusion through the vein on Day 1
Ifosfamide + Mesna (each) 5000 mg/m2 infusion through the vein on Days 1, 2 & 3 or as a single 24hr infusion, the treating clinician will decide which way is best for the patient.

Patients will receive another PET/CT scan prior to commencing Lymphodepleting chemotherapy. This consists of either;
Cyclophosphamide 250mg/m2 Infusion through a vein on D-4, D-3, D-2
& Fludarabine 25mg/m2 Infusion through a vein D-4, D-3, D-2
OR
Cyclophosphamide 250mg/m2 orally with a tablet on D-4, D-3, D-2
& Fludarabine 40mg/m2 orally with a tablet on D-4, D-3, D-2
The treating clinician will decide what is the best route of administration based on the patient, local practice and availability.

They will then receive 3 infusions of CAR T cells through a vein.
The first dose of CAR T cells will be on Day 0 after the Lymphodepleting chemotherapy.
Three dose levels will be explored, there will be 4 weeks gap between each dosing.
1. 1x107cells/metre squared
2. 5 x 107/metre squared
3. 1x108/metre squared
Intervention code [1] 314904 0
Treatment: Drugs
Intervention code [2] 314905 0
Treatment: Other
Comparator / control treatment
No control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320679 0
The accrual rate of newly diagnosed DLBCL patients, this will be assessed by looking at the numbers of patients who have been registered onto the trial who are newly diagnosed.
Timepoint [1] 320679 0
18 months after the enrolment of the first CAR T cell patient (at least 1 infusion received) and again after 6 patients have received CAR T cells,
Primary outcome [2] 320680 0
The number of patients having successful generation of anti-CD19 CAR T cells, this data will be captured in the electronic case report form.
Timepoint [2] 320680 0
18 months after the enrolment of the first CAR T cell patient (at least 1 infusion received) and again after 6 patients have received CAR T cells,
Primary outcome [3] 320681 0
The accrual rate of patients meeting criteria to qualify for anti-CD19 CAR T cells. The numbers of patients meeting the criteria will be assessed.
Timepoint [3] 320681 0
18 months after the enrolment of the first CAR T cell patient (at least 1 infusion received) and again after 6 patients have received CAR T cells,
Secondary outcome [1] 372469 0
Patients Response whether wit will be either of the following;
Complete Response (CR)
Partial Response (PR)
Stable Disease (SD)
or Progressive Disease (PD)
This outcome will be assessed by reviewing patient's medical records, blood results, scans and biopsies.
Timepoint [1] 372469 0
At 4 and 12 weeks following CAR T cell administration.
Final summaries of the time-to-event data will be undertaken when all patients (R-CHOP only, and CAR T cell patients), have reached 2 years after the end of treatment.
Secondary outcome [2] 372470 0
Duration of response, this will be assessed by observing the patients medical records, blood, biopsy results.
Timepoint [2] 372470 0
Defined as the time from the date of first CR to first documented progression / any cause of death.
Final summaries of the time-to-event data will be undertaken when all patients (R-CHOP only, and CAR T cell patients), have reached 2 years after the end of treatment.
Secondary outcome [3] 372471 0
Patient reported outcomes related to well-being. This data will be captured in the following PRO questionnaires: EORTC QLQ-C30 and EuroQol EQ-5D.
Timepoint [3] 372471 0
Patients will be asked to complete questionnaires at the following timepoints
CAR T cell patients
Baseline
4 weeks post 1st infusion
Months 6,9,12

R-CHOP patients
Baseline
3 times a year for 1 year
At the 2 year timepoint.
Secondary outcome [4] 376907 0
Patient reported outcomes related to Health.
This data will be captured in the following PRO questionnaires: EORTC QLQ-C30 and EuroQol EQ-5D.
Timepoint [4] 376907 0
Patients will be asked to complete questionnaires at the following timepoints
CAR T cell patients
Baseline
4 weeks post 1st infusion
Months 6,9,12

Eligibility
Key inclusion criteria
Age 18 - 70 years
Male and female patients
Diagnosis of CD19 and CD20-positive diffuse large B-cell lymphoma on biopsy
ECOG performance status of 0-3
Low-intermediate, high-intermediate, high risk, or low risk disease with bulk (greater than 7.5 cm, please note this measurement also applies for bulky non-nodal disease)
Previously untreated (except for corticosteroids if clinically required)
Patients considered suitable for dose-intense chemotherapy with R-CHOP-21
Eligible and fit for high dose chemotherapy and autologous stem-cell transplantation
Signed informed consent form
A positive baseline FDG PET
Subjects must agree not to donate blood, semen or sperm while on study treatment and for least 12 months after treatment discontinuation
Subjects must agree not to share their medication and to return unused supplies
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Life-expectancy less than 3 months
Transformed NHL, PTLD or types of NHL other than DLBCL
Primary CNS lymphoma or gastrointestinal MALT lymphoma
CD19 and/or CD20-negative NHL
Documented HIV
Seropositivity for Hepatitis B [Either 1. HbsAg (surface antigen) positive or 2. HbcAb (core antibody) positive and HbsAb (surface antibody) titre of less than 100 iu/ml] unless clearly due to vaccination
Patients with good prognosis low risk disease (IPI equals 0, 1) and absence of bulk (less than or equal to 7.5 cm).
Pregnant woman
Previously treated lymphoma
Any serious active disease or co-morbid medical condition including history of seizures (according to investigator’s decision)
Non-compensated cardiac failure
Chronic lung disease with hypoxaemia
Severe psychiatric disease
Poor renal function (creatinine greater than 150 µmol/L), poor hepatic function (total bilirubin level greater than 30 mmol/L, transaminases greater than 2.5 maximum normal level) unless abnormalities are related to the lymphoma
Poor bone marrow reserve as defined by neutrophils less than 1.5 x 109/L or platelets less than 100 x 109/L, unless related to bone marrow infiltration
Any history of cancer during the last 5 years, with the exception of non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma
Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and during the study

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
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 303180 0
Government body
Name [1] 303180 0
Medical Research Future Fund
Country [1] 303180 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
ALLG
34 Elizabeth St
Richmond
Vic 3121
Country
Australia
Secondary sponsor category [1] 303193 0
None
Name [1] 303193 0
Address [1] 303193 0
Country [1] 303193 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 303743 0
The Metro South Hospital and Health Service Human Reasearch Ethics Committee
Ethics committee address [1] 303743 0
Centres for Health Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [1] 303743 0
Australia
Date submitted for ethics approval [1] 303743 0
02/03/2020
Approval date [1] 303743 0
Ethics approval number [1] 303743 0

Summary
Brief summary
Who is this study for
This study is for patients with Primary refractory and early relapsed diffuse large B cell lymphoma.

Treatment
4 cycles of R-CHOP chemotherapy, cycles take place every 3 weeks.
A cycle of R-CHOP consists of
Rituximab 375mg/m2 Infusion through a vein on Day 1
Cyclophosphamide 750mg/m2 infusion through a vein on Day 1
Doxorubicin 50mg/m2 Infusion through a vein on Day 1
Vincristine 1.4mg/m2 (2mg max) Infusion through a vein
Prednisolone 100mg/day once a day for 6 days orally with a tablet

Patients will undergo a PET/CT scan if the patient is refractory they will then go on to receive 2 cycles of R-ICE

A cycle of R-ICE consists of
Rituximab 3752 infusion through the vein on Day 1
Etoposide 100 mg/m2, 20 mins infusion through the vein on Days 1,2 & 3
Carboplatin max 800 mg, 1hr infusion through the vein on Day 1
Ifosfamide + Mesna (each) 5000 mg/m2 infusion through the vein on Days 1, 2 & 3 or as a single 24hr infusion, the treating clinician will decide which way is best for the patient.

Patients will receive another PET/CT scan prior to commencing Lymphodepleting chemotherapy. This consists of either;
Cyclophosphamide 250mg/m2 Infusion through a vein on D-4, D-3, D-2
& Fludarabine 25mg/m2 Infusion through a vein D-4, D-3, D-2
OR
Cyclophosphamide 250mg/m2 orally with a tablet on D-4, D-3, D-2
& Fludarabine 40mg/m2 orally with a tablet on D-4, D-3, D-2
The treating clinician will decide what is the best route of administration based on the patient, local practice and availability.

They will then receive 3 infusions of CAR T cells through a vein.
The first dose of CAR T cells will be on Day 0 after the Lymphodepleting chemotherapy.
Three dose levels will be explored, there will be 4 weeks gap between each dosing.
1. 1x107cells/m2
2. 5 x 107/m2
3. 1x108/m2.

Patients will undergo blood testing, PET/CT scans and questionnaires throughout the study.
The aim of this study is to improve the health outcomes of patient diagnosed with Primary refractory and early relapsed diffuse large B cell lymphoma by administering CAR T Cells early in their treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94642 0
Prof Maher Gandhi
Address 94642 0
Princess Alexandra Hospital
Raymond Terrace,
Mater Research
Aubigny Place
Level 3
South Brisbane
Qld 4101
Country 94642 0
Australia
Phone 94642 0
+61 3 83739701
Fax 94642 0
Email 94642 0
maher.gandhi@mater.uq.edu.au
Contact person for public queries
Name 94643 0
Ms Delaine Smith
Address 94643 0
ALLG
35 Elizabeth St
Richmond
Vic 3121
Country 94643 0
Australia
Phone 94643 0
+61 03 83739701
Fax 94643 0
Email 94643 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 94644 0
Ms Delaine Smith
Address 94644 0
ALLG
35 Elizabeth St
Richmond
Vic 3121
Country 94644 0
Australia
Phone 94644 0
+61 03 83739701
Fax 94644 0
Email 94644 0
delaine.smith@allg.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be shared publically. Aggregate patient data and final results will be presented in the final report.


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.