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Trial registered on ANZCTR


Registration number
ACTRN12619000079145
Ethics application status
Approved
Date submitted
17/01/2019
Date registered
21/01/2019
Date last updated
21/01/2019
Date data sharing statement initially provided
21/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety of Immune Cells for Patients with Relapsed Leukaemia or Lymphoma after Chemotherapy
Scientific title
A Phase I Study of Autologous CD19 Specific Chimeric Antigen Receptor T-cells for Therapy of Relapsed and Refractory B-cell Leukaemia and Lymphoma
Secondary ID [1] 297107 0
None
Universal Trial Number (UTN)
U1111-1226-8682
Trial acronym
The AutoCAR19 Trial
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Acute Lymphoblastic Leukaemia 311118 0
Chronic Lymphocytic Leukaemia 311119 0
Non-Hodgkins Lymphoma 311120 0
Condition category
Condition code
Cancer 309753 309753 0 0
Leukaemia - Acute leukaemia
Cancer 309754 309754 0 0
Leukaemia - Chronic leukaemia
Cancer 309755 309755 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 309756 309756 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 autologous CD19-specific chimeric antigen receptor (CAR19) T-cells for relapsed or persistent B-cell malignancy after standard chemotherapy.

Patients will have T-cells collected from their blood by leukapheresis. This involves having drips placed into the large veins in the patient's arms which are then connected to an apheresis machine for several hours. These T-cells will undergo genetic modification in the laboratory to express the CAR19 and be frozen for administration to the patient once they are ready to receive them.

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.

Autologous CAR19 T-cells will be administered intravenously after lymphodepleting cyclophosphamide 250mg/m^2 and fludarabine 40mg/m^2 tablets taken orally, daily on days -4 to -2 prior to CAR19 T-cell administration by intravenous injection 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] 313375 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 318713 0
Early Safety

Incidence of grade 3 or higher toxicity as defined by the US National Cancer Institute Common Toxicity Criteria Scale
Timepoint [1] 318713 0
4 weeks after each CAR19 T-cell dose
Secondary outcome [1] 365785 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] 365785 0
4 weeks after each CAR19 T-cell dose
Secondary outcome [2] 365786 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] 365786 0
4 weeks after each CAR19 T-cell dose
Secondary outcome [3] 365787 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] 365787 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] 365788 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] 365788 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 [5] 365789 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] 365789 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 relapsed or refractory disease after standard therapy. Disease may be identified by clinical examination, radiology, nuclear imaging, flow cytometry or molecular biological methods. To qualify for enrolment, patients must have one of the following:
-Refractory CD19+ high grade NHL- defined as less than 50% reduction in lymph node size (nodes >2cm) or persisting organ enlargement or the appearance of new lymphadenopathy, hepatosplenomegaly or marrow involvement after chemotherapy or Deauville 5 PET positive disease on interim PET scan after 4 cycles of chemotherapy
- Relapsed CD19+ high grade NHL ineligible for autologous stem cell transplant or after autologous stem cell transplant
-Refractory CD19+ low grade NHL- defined as less than 50% reduction in lymph node size (nodes >2cm) or persisting organ enlargement or the appearance of new lymphadenopathy, hepatosplenomegaly or marrow involvement after chemotherapy
-Relapsed CD19+ low grade NHL less than 12 months from chemotherapy or third or greater relapse
-Refractory CLL defined as resistance to purine analogues with less than 50% reduction in lymph node size (nodes >2cm) and/or lymphocytosis, or persisting organ enlargement after initial therapy or progression/relapse requiring therapy less than 6 months post chemotherapy.
-CLL Richters transformation
-Persistent CD19+ ALL after consolidation, defined as not in CR by morphology, flow, cytogenetics or molecular methods after induction chemotherapy (includes MRD at or above threshold as assessed by flow cytometry or molecular methods)
-Relapsed CD19+ ALL as assessed by morphology, flow, cytogenetics or molecular methods at any time point during or after standard therapy

2. Karnofsky/Lansky score greater than or equal to 50%, or ECOG less than or equal to 2.
3. 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.
4. 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. Bilirubin >2x upper limit of normal, AST >3x upper limit of normal, creatinine >2x upper limit of normal for age.
3. Pulse oximetry greater than or equal to 90% on room air.
4. Pregnant or lactating.
5. History of hypersensitivity reactions to murine protein-containing products.
6. 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. Patients will receive up to 3 doses of autologous 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 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 in 7 of 16 patients (44%, 95% CI 20-68%), predominantly in the group of patients with morphologically detectable ALL (approximately 80% of patients with morphologically detectable disease).
We intend to recruit 20 patients over 2 years. Interim monitoring for rates of sCRS will be performed 100 days after the tenth patient has received CAR19 T-cells. If 8 or more cases of sCRS 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 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, accrual will continue to a total of 20, while if 12 or more sCRS 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 the trial will be placed on hold and data reviewed by the 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
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,WA,VIC
Recruitment hospital [1] 12927 0
Westmead Hospital - Westmead
Recruitment hospital [2] 12928 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 12929 0
Sydney Children's Hospital - Randwick
Recruitment hospital [4] 12930 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 12931 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [6] 12932 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [7] 12933 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [8] 12934 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [9] 12935 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [10] 12936 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [11] 12937 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 25402 0
2145 - Westmead
Recruitment postcode(s) [2] 25403 0
2031 - Randwick
Recruitment postcode(s) [3] 25404 0
4029 - Herston
Recruitment postcode(s) [4] 25405 0
4101 - South Brisbane
Recruitment postcode(s) [5] 25406 0
3000 - Melbourne
Recruitment postcode(s) [6] 25407 0
3050 - Parkville
Recruitment postcode(s) [7] 25408 0
5000 - Adelaide
Recruitment postcode(s) [8] 25409 0
5006 - North Adelaide
Recruitment postcode(s) [9] 25410 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 301672 0
Government body
Name [1] 301672 0
National Health and Medical Research Council
Address [1] 301672 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 301672 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] 301389 0
None
Name [1] 301389 0
NA
Address [1] 301389 0
NA
Country [1] 301389 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302391 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 302391 0
Research Office, Level 2, REN Building
Westmead hospital
Hawkesbury and Darcy Roads
Westmead NSW 2145
Ethics committee country [1] 302391 0
Australia
Date submitted for ethics approval [1] 302391 0
17/08/2015
Approval date [1] 302391 0
20/06/2016
Ethics approval number [1] 302391 0
HREC/15/WMEAD/362

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

Who is it for?
You may be eligible to join this study if you have persistent or relapsed B-cell malignancy after standard chemotherapy.

Study details
Patient 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 90074 0
Dr Kenneth Micklethwaite
Address 90074 0
Clinical Support 1 Crown Princess Mary Cancer Centre
Westmead Hospital
Hawkesbury Rd
Westmead NSW 2145
Country 90074 0
Australia
Phone 90074 0
+61288905764
Fax 90074 0
+61288906391
Email 90074 0
kenneth.micklethwaite@sydney.edu.au
Contact person for public queries
Name 90075 0
Dr Kenneth Micklethwaite
Address 90075 0
Clinical Support 1 Crown Princess Mary Cancer Centre
Westmead Hospital
Hawkesbury Rd
Westmead NSW 2145
Country 90075 0
Australia
Phone 90075 0
+61 288905764
Fax 90075 0
+61288906391
Email 90075 0
kenneth.micklethwaite@sydney.edu.au
Contact person for scientific queries
Name 90076 0
Dr Kenneth Micklethwaite
Address 90076 0
Clinical Support 1 Crown Princess Mary Cancer Centre
Westmead Hospital
Hawkesbury Rd
Westmead NSW 2145
Country 90076 0
Australia
Phone 90076 0
+61288905764
Fax 90076 0
+61288906391
Email 90076 0
kenneth.micklethwaite@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
de-identified individual participant data used for published results.
When will data be available (start and end dates)?
Immediately following publication with no end date.
Available to whom?
Researchers who provide a methodologically sound, ethics committee approved proposal.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Access via individual secure data transfer with approval by the Principal Investigator and Institutional Ethics Committee.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Summary results
No Results