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Trial registered on ANZCTR


Registration number
ACTRN12617001579381
Ethics application status
Approved
Date submitted
4/11/2017
Date registered
27/11/2017
Date last updated
1/11/2018
Date data sharing statement initially provided
1/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety of Immune Cells for Patients with Relapsed Leukaemia or Lymphoma after Bone Marrow Transplant
Scientific title
A Phase I Study of CD19 Specific Chimeric Antigen Receptor T-cells for Therapy of Persistent and Relapsed B-cell Leukaemia and Lymphoma Post Allogeneic Stem Cell Transplantation
Secondary ID [1] 293283 0
None
Universal Trial Number (UTN)
U1111-1204-6974
Trial acronym
The CARTELL Study
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Acute Lymphoblastic Leukaemia 305359 0
Chronic Lymphocytic Leukaemia 305360 0
Non-Hodgkins Lymphoma 305361 0
Condition category
Condition code
Cancer 304641 304641 0 0
Leukaemia - Acute leukaemia
Cancer 304642 304642 0 0
Leukaemia - Chronic leukaemia
Cancer 304643 304643 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 304644 304644 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Up to 20 patients will receive allogeneic matched sibling donor derived CD19-specific chimeric antigen receptor (CAR19) T-cells for relapsed or persistent B-cell malignancy detected at any time post allogeneic stem cell transplant.

Patients with active disease requiring therapy while CAR19 T-cells are being prepared will receive chemotherapy or radiotherapy as appropriate determined by the patient's usual treating physician.

Matched related donor derived CAR19 T-cells will be administered intravenously after lymphodepleting cyclophosphamide 250mg/m^2 IV and fludarabine 25mg/m^2 IV daily on days -4 to -2 prior to CAR19 T-cell administration on day 0.

Three CAR19 T-cell dose levels will be assessed within each patient: 1x10^7cells/m^2, 5x10^7cells/m^2 and 1x10^8/m^2. Patients will receive 1 dose only at each level. Dose escalation will be determined 4 weeks after the last dose dependent on persistence of disease, no severe toxicity and falling CAR19 T-cell numbers.
Intervention code [1] 299538 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303868 0
Early Safety

Incidence of grade 3 or higher toxicity as defined by the US National Cancer Institute Common Toxicity Criteria Scale
Timepoint [1] 303868 0
4 weeks after each CAR19 T-cell dose
Secondary outcome [1] 340317 0
Short Term Persistence of CAR19 T-cells

Levels of CAR19 T-cells quantified by established immunological including flow cytometry and ELISPOT, and molecular assays such as PCR detection of the CAR transgene
Timepoint [1] 340317 0
4 weeks after each CAR19 T-cell dose
Secondary outcome [2] 340318 0
Early Disease Response

Lymphoma and leukaemia response and levels of minimal residual disease will be assessed by standard radiological imaging, and morphological, cytometric and molecular analysis of peripheral blood and bone marrow.
Timepoint [2] 340318 0
4 weeks after each CAR19 T-cell dose
Secondary outcome [3] 340319 0
Long Term Safety

Assessment of long term side effects such as B-cell aplasia and genotoxicity by routine full blood count and immunoglobulin levels.
Timepoint [3] 340319 0
Indefinitely (minimum of 15 years in survivors)
Survivors beyond 12 months will be seen as clinically indicated at least 6 monthly for the proceeding four years and then at least yearly lifelong for detection of long term toxicity of CAR19 T-cells.
Secondary outcome [4] 340320 0
Long Term Persistence of CAR19 T-cells

Levels of CAR19 T-cells quantified by established immunological including flow cytometry and ELISPOT, and molecular assays such as PCR detection of the CAR transgene.
Timepoint [4] 340320 0
Indefinitely (minimum of 15 years in survivors)
Survivors beyond 12 months will be seen as clinically indicated at least 6 monthly for the proceeding four years and then at least yearly lifelong.
Secondary outcome [5] 340321 0
Long Term Disease Response

Lymphoma and leukaemia response and levels of minimal residual disease will be assessed by standard radiological imaging, and morphological, cytometric and molecular analysis of peripheral blood and bone marrow.
Timepoint [5] 340321 0
Indefinitely (minimum of 15 years in survivors)
Survivors beyond 12 months will be seen as clinically indicated at least 6 monthly for the proceeding four years and then at least yearly lifelong.

Eligibility
Key inclusion criteria
1. Any patient regardless of sex or age with persistent or recurrent disease after a matched related allogeneic stem cell transplant performed for CD19+ lymphoid malignancies. Disease may be identified by clinical examination, radiology, nuclear imaging, flow cytometry or molecular biological methods.
2. Life expectancy greater than or equal to 6 weeks.
3. Karnofsky/Lansky score greater than or equal to 50%, or ECOG less than or equal to 2.
4. Donor willing and available to donate peripheral blood for the generation of CAR19 T-cells.
5. Sexually active patients must be willing to utilise one of the more effective birth control methods for 6 months after the CTL infusion. Male partners should use a condom.
6. Donor and patient and/or parent/guardian capable of providing informed consent.
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Uncontrolled inter-current infection.
2. Graft versus host disease greater than or equal to grade II.
3. Unmanipulated donor lymphocyte infusion within the previous 10 weeks.
4. Corticosteroid dose greater than the equivalent of 0.5mg/kg of oral prednisolone.
5. Bilirubin >2x upper limit of normal, AST >3x upper limit of normal, creatinine >2x upper limit of normal for age.
6. Pulse oximetry less than or equal to 90% on room air.
7. Pregnant or lactating.
8. History of hypersensitivity reactions to murine protein-containing products.
9. History of seizures.

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)
Not Applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not Applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Intrapatient dose escalation study of a biological therapy
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a non-randomised Phase I safety and biological efficacy study. Allogeneic stem cell transplant patients will receive escalating doses of donor derived CAR19 T-cells every 4 weeks after detection of relapsed or persistent B-cell malignancy. T-cells will be given either alone or as an adjunct to further salvage chemotherapy. All infusions will be administered after T-cell depleting cyclophosphamide and fludarabine to maximise expansion of donor CAR19 T-cells. Recipients will be monitored for toxicity and detection of transduced T-cells, as well as disease specific markers. The major serious adverse event seen in patients receiving CAR19 T-cells to date has been the severe cytokine release syndrome. This occurred predominantly in the group of patients with morphologically detectable ALL (approximately 80% of patients with morphologically detectable disease). Given the allogeneic origin of the CAR19 T-cells for infusion, graft versus host disease is the other major serious potential adverse event. Various studies show an overall rate of graft versus host disease post unmanipulated donor lymphocyte infusion for B-cell malignancies of up to 75% (99% CI 19-99%)206, with severe acute or chronic GVHD of approximately 30% (95% CI 16-44%).
We intend to recruit 20 patients over 2 years. Interim monitoring for rates of sCRS and severe GVHD (acute GVHD grades III-IV and extensive chronic GVHD) will be performed 100 days after the tenth patient has received CAR19 T-cells. If 8 or more cases of sCRS or 6 or more cases of severe GVHD are observed, the trial will be placed on hold and data reviewed by the data safety monitoring committee (DSMC) to determine if the trial can proceed (This review will be in addition to scheduled DSMC meetings). If less than 8 cases of sCRS and less than 6 cases of severe GVHD are observed, the trial will continue to accrue without the need for additional DSMC review. Similarly, if after 15 patients are enrolled there are less than 12 cases of sCRS and less than 9 severe GVHD, accrual will continue to a total of 20, while if 12 or more sCRS cases or 9 or more severe GVHD cases are observed the regimen will be re-assessed by the DSMC. These boundaries are based on the charts of Mehta and Cain. In addition, if there are any deaths related to sCRS or GVHD the trial will be placed on hold and data reviewed by the data safety monitoring committee (DSMC) to determine if the trial can proceed.
Adverse event data and corresponding toxicity grades four weeks after T-cell infusions will be summarized in the form of tables. Descriptive statistics will be used to summarise laboratory safety data as well as T-cell persistence and levels of disease.

Recruitment
Recruitment status
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
Recruitment hospital [1] 9341 0
Westmead Hospital - Westmead
Recruitment hospital [2] 9342 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 9343 0
Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 18016 0
2145 - Westmead
Recruitment postcode(s) [2] 18017 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 297909 0
Government body
Name [1] 297909 0
National Health and Medical Research Council
Address [1] 297909 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 297909 0
Australia
Primary sponsor type
Hospital
Name
Western Sydney Local Health District, Westmead Hospital
Address
Westmead Hospital
Hawkesbury Rd
Westmead NSW 2145
Country
Australia
Secondary sponsor category [1] 296967 0
None
Name [1] 296967 0
NA
Address [1] 296967 0
NA
Country [1] 296967 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298959 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 298959 0
Research Office, Level 2, REN Building
Westmead hospital
Hawkesbury and Darcy Roads
Westmead NSW 2145
Ethics committee country [1] 298959 0
Australia
Date submitted for ethics approval [1] 298959 0
13/08/2014
Approval date [1] 298959 0
09/12/2014
Ethics approval number [1] 298959 0
(4089) AU RED HREC/14/WMEAD/332

Summary
Brief summary
The aim of this project is to evaluate the Safety of Immune Cells for Patients with Relapsed Leukaemia or Lymphoma after Bone Marrow Transplant.

Who is it for?
You may be eligible to join this study if you have persistent or relapsed B-cell malignancy post related donor allogeneic stem cell transplant and a donor willing and available to donate peripheral blood for the generation of CAR19 T-cells.

Study details
Matched related donor derived CAR19 T-cells will be administered intravenously after lymphodepleting cyclophosphamide and fludarabine. This T-cell therapy may be administered alone or in addition to salvage chemotherapy. Three CAR19 T-cell dose levels will be assessed within each patient: 1x10^7cells/m^2, 5x10^7cells/m^2 and 1x10^8/m^2. Dose escalation will be determined 4 weeks after the last dose dependent on persistence of disease, no severe toxicity and falling CAR19 T-cell numbers. Patients will be monitored for early and long term toxicity, persistence of CAR T-cells and disease response.

If successful, this treatment will enable the widespread application of CAR19 T-cells to patients with few other effective treatment options.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78794 0
Dr Kenneth Micklethwaite
Address 78794 0
Clinical Support 1 Crown Princess Mary Cancer Centre
Westmead Hospital
Hawkesbury Rd
Westmead NSW 2145
Country 78794 0
Australia
Phone 78794 0
+61288905764
Fax 78794 0
+61288906391
Email 78794 0
kenneth.micklethwaite@sydney.edu.au
Contact person for public queries
Name 78795 0
Dr Kenneth Micklethwaite
Address 78795 0
Clinical Support 1 Crown Princess Mary Cancer Centre
Westmead Hospital
Hawkesbury Rd
Westmead NSW 2145
Country 78795 0
Australia
Phone 78795 0
+61288905764
Fax 78795 0
+61288906391
Email 78795 0
kenneth.micklethwaite@sydney.edu.au
Contact person for scientific queries
Name 78796 0
Dr Kenneth Micklethwaite
Address 78796 0
Clinical Support 1 Crown Princess Mary Cancer Centre
Westmead Hospital
Hawkesbury Rd
Westmead NSW 2145
Country 78796 0
Australia
Phone 78796 0
+61288905764
Fax 78796 0
+61288906391
Email 78796 0
kenneth.micklethwaite@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Considering ways of ensuring the privacy of individuals is maintained.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Summary results
No Results