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Trial registered on ANZCTR


Registration number
ACTRN12618001540202
Ethics application status
Approved
Date submitted
11/09/2018
Date registered
14/09/2018
Date last updated
19/02/2020
Date data sharing statement initially provided
20/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Fungus-specific immune cells for bone marrow transplant patients with invasive fungal disease
Scientific title
A phase 1 trial of HLA-DR matched third party donor-derived fungus-specific cytotoxic T-lymphocytes in patients with invasive fungal disease post-allogeneic stem cell transplantation
Secondary ID [1] 295529 0
None
Universal Trial Number (UTN)
NA
Trial acronym
R3ACT Fungal
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
Invasive Fungal Disease 308794 0
Condition category
Condition code
Infection 307731 307731 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase 1 trial of three dose levels of third party, donor-derived fungus-specific cytotoxic T-lymphocytes (CTL's) in patients with invasive fungal disease post-allogeneic stem cell transplantation. Patients will initially be given a dose of 1x10^6cells/m^2 followed by 1x10^7cells/m^2 and 1x10^8cells/m^2 no less than 14 days and no more than 3 months apart. The decision to proceed with the next infusion will be in the opinion of the treating physician and the Chief Investigator if it is in the patient’s best interest to do so. Factors such as toxicity from previous infusions, response of disease to previous infusion and concomitant medications will be considered. The infusion will be given via intravenous infusion over 5 minutes. The patient may receive the infusion as an outpatient (eg: Cancer Day Suite) but it is recommended that they remain in hospital for at least 7 days after the administration of T-cells for monitoring of potential complications of therapy. Given the patient disease it is likely they will already be an inpatient.
Intervention code [1] 301838 0
Treatment: Other
Comparator / control treatment
NA
Control group
Uncontrolled

Outcomes
Primary outcome [1] 306720 0
Safety of CTL infusion
Measured by Grade 3 (as defined by CTC version 4) or above adverse events and toxicities attributed to the infusion by the investigator such as Graft versus host disease. Information will be collected from the medical records.
Timepoint [1] 306720 0
From administration of first infusion to 12 months after the final infusion
Secondary outcome [1] 349330 0
Clinical response of invasive fungal disease
As measured by Serum galactomannan/fungal PCR and clinical/radiological assessment based on characteristics of disease at diagnosis
Timepoint [1] 349330 0
Pre-infusion then fortnightly for 6 weeks and monthly for the following 2 months post-infusion
Secondary outcome [2] 349331 0
Survival post-CTL infusion
Timepoint [2] 349331 0
At 3 months and 6 month time-point post-infusion most recent infusion. Patients will be seen for review. If this is not possible, investigators will make a telephone call to the patient.
Secondary outcome [3] 349332 0
Fungal specific immune reconstitution as measured by laboratory results such as neutrophil count.
Timepoint [3] 349332 0
At 1 and 3 months initial infusion
Secondary outcome [4] 349333 0
Use of systemic anti-fungal pharmacotherapy as documented in medical records
Timepoint [4] 349333 0
Within the 6 months post first infusion
Secondary outcome [5] 349334 0
Incidence of acute Graft versus host disease (GVHD) determined by review of medical records documenting the presence and extent of clinical and histological features consistent with this diagnosis..
Timepoint [5] 349334 0
From initial infusion to 12 months after final infusion
Secondary outcome [6] 349335 0
Number of in-hospital days measured from medical record
Timepoint [6] 349335 0
Within 6 months after the initial infusion
Secondary outcome [7] 349336 0
Recurrence of invasive fungal disease as measured by clinical or radiological assessment to diagnose disease (eg: CT scan)
Timepoint [7] 349336 0
Within 6 months after the infusion
Secondary outcome [8] 349337 0
Graft function as measured by laboratory results such as neutrophil and platelet recovery
Timepoint [8] 349337 0
At 1, 3 and 6 months after first infusion
Secondary outcome [9] 349338 0
Persistence of infused T-cells measured from laboratory results. (eg: Number of cells present in serum)
Timepoint [9] 349338 0
Pre-infusion,
After infusion: daily for 1 week, weekly for 3 further weeks, fortnightly for 1 month than monthly for a further 2 months.
Secondary outcome [10] 349339 0
Correlation of response with degree of HLA matching
Timepoint [10] 349339 0
As measured by HLA results pre-infusion in correlation with disease response 6 and 12 months after the final infusion
Secondary outcome [11] 349346 0
Incidence of chronic Graft Versus Host Disease (GVHD) determined by review of medical records documenting the presence and extent of clinical and histological features consistent with this diagnosis..
Timepoint [11] 349346 0
From initial infusion to 12 months after final infusion

Eligibility
Key inclusion criteria
- Recipients of myeloablative or non-myeloablative allogeneic stem cell transplantation from HLA-matched family or unrelated donor, mismatched family or unrelated donor or cord blood donor
- Proven or probable invasive fungal disease following transplant as defined by the internationally accepted criteria of the European Organisation for Research and Treatment of Cancer and the US-based Mycoses Study Group within 1 year of allogeneic stem cell transplant
- Patients has received no more than 28 days of a therapeutic dose of an anti-fungal drug prior to fungus-specific T-cell infusion (prophylactic anti-fungal agents not included). The choice of anti-fungal agents will be unrestricted and at the discretion of the treating physician
- Adequate hepatic and renal function (< 5 x upper limit of normal for AST (SGOT), ALT (SGPT), < 3 x upper limit of normal for total bilirubin, serum creatinine)
- ECOG status 0 to 3 or Lansky score 30-100
- Patient (or legal representative) has given informed consent.
Minimum age
1 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Use of anti-lymphocyte globulin (ALG, ATG, Campath or other broad spectrum lymphocyte antibody) in the 4 weeks immediately prior to fungus-specific T-cell infusion or planned within 4 weeks after infusion unless anti-lymphocyte globulin levels in blood shown to be below the lympholytic threshold prior to infusion.
- Active grade II or greater graft versus host disease within 1 week prior to infusion.
- Prednisone or methylprednisolone at a dose of > 1 mg/kg daily (or equivalent in other steroid preparations) administered within 72 hours prior to cell infusion.
- Dose of prednisone or methylprednisolone (if administered) not maintained at a stable level for 72 hours prior to T cell infusion
- Active and uncontrolled relapse of malignancy
- Severe peripheral cytopenia (ANC <0.5 x 10^9/L, platelet count <20 x 10^9/L unsupported)
- Active uncontrolled non-fungal infection including bacterial sepsis requiring commencement of systemic intravenous antibiotics in the 48 hours prior to T-cell infusion, active tissue infection with opportunistic viruses or untreated or progressing post-transplant lymphoproliferative disease
- Hypotension requiring fluid or pressor support, hypoxia or neurological features such as confusion or seizures in the 48 hours prior to T-cell infusion
- Patients requiring assisted respiration (eg: CPAP/intubation)
- ECOG status 4 or Lansky score <30
- Privately insured in or outpatients in New South Wales participating centres


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



Intervention assignment
Single group
Other design features
NA
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis
The number of patients to be recruited will be determined by the rate of adverse events at the three dose levels specified. The adult and paediatric Bone Marrow
Transplant Units at Westmead Hospital perform approximately 100 allogeneic stem cell transplants annually. Allowing for a dropout rate of 50% based on co-morbidities, exclusions and refusal, approximately 3 patients annually will be recruited to the study.

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,VIC
Recruitment hospital [1] 11428 0
Westmead Hospital - Westmead
Recruitment hospital [2] 11429 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 23435 0
2145 - Westmead
Recruitment postcode(s) [2] 23436 0
2145 - Wentworthville

Funding & Sponsors
Funding source category [1] 300109 0
Charities/Societies/Foundations
Name [1] 300109 0
Cancer Council NSW
Address [1] 300109 0
43 Hunter Street, Parramatta, NSW, Australia, 2150
Country [1] 300109 0
Australia
Primary sponsor type
Hospital
Name
Western Sydney Local Health District
Address
Cnr Hawkesbury and Darcy Roads, Westmead, NSW, 2145
Country
Australia
Secondary sponsor category [1] 300154 0
None
Name [1] 300154 0
Address [1] 300154 0
Country [1] 300154 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300951 0
Western Sydney Local Health District HREC
Ethics committee address [1] 300951 0
Westmead Research Office
Research & Education Network Building
Westmead Hospital
Darcy Road
Westmead
NSW
2145
Ethics committee country [1] 300951 0
Australia
Date submitted for ethics approval [1] 300951 0
10/07/2018
Approval date [1] 300951 0
07/09/2018
Ethics approval number [1] 300951 0
AU RED HREC/18/WMEAD/236

Summary
Brief summary
Fungal infections after receiving a bone marrow transplant is lethal and requires costly anti-fungal treatment . This study will give immune cells to transplant patients to fight the infection. We hope that these immune cells will shorten the amount of anti-fungal drugs required and improve patient outcomes.
Trial website
NA
Trial related presentations / publications
NA
Public notes

Contacts
Principal investigator
Name 85390 0
Prof David Gottlieb
Address 85390 0
Westmead Hospital, Westmead, NSW, 2145
Country 85390 0
Australia
Phone 85390 0
+61 2 8890 9269
Fax 85390 0
+61 2 9689 3700
Email 85390 0
david.gottlieb@sydney.edu.au
Contact person for public queries
Name 85391 0
Ms Elissa Atkns
Address 85391 0
Westmead Hospital, Westmead, NSW, 2145
Country 85391 0
Australia
Phone 85391 0
+61 2 8890 9269
Fax 85391 0
+61 2 9689 3700
Email 85391 0
Elissa.Atkins@health.nsw.gov.au
Contact person for scientific queries
Name 85392 0
Ms Elissa Atkns
Address 85392 0
Westmead Hospital, Westmead, NSW, 2145
Country 85392 0
Australia
Phone 85392 0
+61 2 8890 9269
Fax 85392 0
+61 2 9689 3700
Email 85392 0
Elissa.Atkins@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Report will comment of participants as a whole
What supporting documents are/will be available?
No other documents available
Summary results
No Results