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Trial registered on ANZCTR


Registration number
ACTRN12618000661279
Ethics application status
Approved
Date submitted
13/03/2018
Date registered
24/04/2018
Date last updated
18/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I study investigating the mean circulation time, biodistribution and safety of an infusion of cultured red cells (CRC) in patients with myelodysplastic syndrome (MDS) or patients in remission from haematologic malignancy
Scientific title
A phase I study investigating the mean circulation time, biodistribution and safety of an infusion of chromium isotope 51 labelled cultured red cells (CRC) in patients with MDS or patients in remission from haematologic malignancy.
Secondary ID [1] 294319 0
None
Universal Trial Number (UTN)
U1111-1210-8666
Trial acronym
CRC
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
haematologic malignancy in remission and not on active treatment 307034 0
very-low or low risk myelodysplastic syndrome 307035 0
Condition category
Condition code
Cancer 306134 306134 0 0
Other cancer types
Blood 306135 306135 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will have a single infusion of Chromium isotope 51 (51Cr) labelled, biotinylated Cultured Red Cells at a dose of 0.7-1.5 x10^10 cells. The infusion will be administered over 15 minutes by nuclear medicine technicians.
As this is a single infusion performed under observation to monitoring of adherence is required.
The initial phase will include 4 patients. If there are no safety concerns then the sponsor may elect to proceed to the expansion phase with the inclusion of 6 additional patients. The dose of cells is the same in the initial and the expansion phase.
Intervention code [1] 300625 0
Treatment: Other
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 305154 0
• To evaluate the mean cell circulation time using 51Cr labelling
Timepoint [1] 305154 0
Monitoring will occur on Days 0, Days 1, 2, 4, 6, 8, 11, 13, 15, 18, 20, 22, 25, 27, 45, 60, 90 and 120 post infusion.
As the half-life of chromium is 27 days. This primary timepoint will be assessed after day 27 post infusion.
Primary outcome [2] 305323 0
• To evaluate the biodistribution of CRC
Timepoint [2] 305323 0
Monitoring will occur on Days 0, Days 1, 2, 4, 6, 8, 11, 13, 15, 18, 20, 22, 25, 27, 45, 60, 90 and 120 post infusion.
As the half-life of chromium is 27 days. This primary timepoint will be assessed after day 27 post infusion.
This will be determined by plotting radioactive counts in peripheral blood tests per mL against time from the infusion of cultured red cells. A line of best fit will be modelled using the standard method described here: Recommended method for radioisotope red-cell survival studies. International Committee for Standardization in Haematology. Br J Haematol 1980;45:659–666
Primary outcome [3] 305324 0
• To evaluate the safety and tolerability of CRC when administered intravenously (IV) as a single infusion
Timepoint [3] 305324 0
Monitoring will occur on Days 0, Days 1, 2, 4, 6, 8, 11, 13, 15, 18, 20, 22, 25, 27, 45, 60, 90 and 120 post infusion.
This timepoint will be assessed following the day 120 assessment or earlier if an adverse event is identified.
Patients will have vital signs, clinical review and blood tests at each time point above or as required. Blood tests will look for evidence of increased red cell turnover (elevated LDH, bilirubin, reticulocyte count, reduced haptoglobin) or the development of alloantibodies (positive direct antiglobulin or indirect antiglobulin tests).
Secondary outcome [1] 344340 0
To evaluate the immunogenicity of CRC as assessed by development of alloantibodies up to 120 days after infusion.
This is determined by performing an indirect antiglobulin test and tests to assess for haemolysis including reticulocyte count, LDH, bilirubin and haptoglobin.

Timepoint [1] 344340 0
Monitoring will occur on Days 0, Days 1, 2, 4, 6, 8, 11, 13, 15, 18, 20, 22, 25, 27, 45, 60, 90 and 120 post infusion.
This endpoint will be assessed after day 120 post-infusion or earlier if an adverse event is identified.
Secondary outcome [2] 344840 0
To evaluate alternative methods of determining mean cell circulation time using Biotinylation and flow cytometry in comparison to 51Cr labelling.
Timepoint [2] 344840 0
Monitoring will occur on Days 0, Days 1, 2, 4, 6, 8, 11, 13, 15, 18, 20, 22, 25, 27, 45, 60, 90 and 120 post infusion.
This endpoint will be assessed after day 120 post-infusion.

Eligibility
Key inclusion criteria
• Patients has either:
o very-low or low-risk MDS as defined by the IPSS-R (Score 0-3); or
o previous haematologic malignancy in remission.
• Patient has required at least one unit of packed red cells since the time of MDS or haematologic malignancy diagnosis.
• Patient is greater than or equal to 18 years of age
• Patient has provided written confirmation of informed consent on participant information and consent form
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Estimated life expectancy greater than or equal to 1 year.
• Adequate organ function as defined below:
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 1.5 x upper limit of normal (ULN); if liver function abnormalities are due to the underlying malignancy, then AST and ALT must be less than or equal to 2.5 x ULN;
• Total serum bilirubin less than or equal to ULN unless due to Gilbert’s Syndrome;
• Serum creatinine less than or equal to 1.25 x ULN; or if serum creatinine > 1.25 x ULN, then calculated (Cockcroft-Gault formula) glomerular filtration rate (GFR) greater than or equal to 60 mL/min;
• Haemoglobin (Hb) greater than or equal to 9.0 g/dL
• Absolute neutrophil count greater than or equal to 1,000/mm3 (not supported by growth factors in the preceding 1 month);
• Platelet count greater than or equal to 80,000/mm3 (without platelet transfusion or growth factor support in the preceding 1 month);
• Activated partial thromboplastin time (aPTT) less than or equal to 1.25 x ULN and international normalized ratio (INR) less than or equal to 1.3 (unless the subject is receiving therapeutic anticoagulants);
• Folate and Vitamin B12 levels WNL within 90 days prior to registration;
• Adequate iron status defined as serum ferritin greater than 20 ng/ml and transferrin saturation of greater than 30% within 90 days prior to registration;
• Haemolysis panel (serum bilirubin WNL; serum LDH less than or equal to the ULN; serum haptoglobin WNL; urine haemosiderin undetectable).
• Antibody screen negative on extended blood-typing panel.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patients with intermediate to very-high risk MDS (IPSS-R score >3)
• Patients with active haematologic malignancy (excluding very-low or low risk MDS)
• Patients with symptomatic anaemia who require red blood cell transfusions of one or more units of packed cells more frequently than every two months.
• Patients who have received treatment with anti-cancer therapy (including but not be limited to chemotherapy, immunotherapy, biological therapy, targeted therapy or hormonal therapy within) within 3 months of registration.
• Concurrently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo.
• Concurrent medical conditions that in the judgment of the investigator will interfere with the objectives of the study or safety, including:
• History of haemolytic anaemia or autoimmune disorders that can affect red blood cell circulation times in the opinion of the investigator;
• Splenomegaly detectable by physical examination or radiographic assessment;
• Hepatomegaly detectable by physical examination or radiographic assessment;
• Clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, oncologic, or psychiatric disease,
• Acute myocardial infarction, deep venous thrombosis or pulmonary embolism within 6 months of registration;
• Prior bone marrow or stem cell transplant;
• Previously known infection with human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C (HCV).
• Any active infection requiring the use of parenteral anti-microbial agents or that is > Grade 2.
• Patient has not recovered from the adverse effects of previous treatments to pre-treatment baseline or Grade 1 by registration.
• Patients with known hypersensitivity to any component/excipient used in this study.
• Patients with previous transfusion reactions greater than Grade 1 reactions.
• Women of childbearing potential
• Patients whose primary language is other than English will be excluded from this study given 1) there is no clinical benefit for patients on this study and 2) the complexity of the information to be absorbed.

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
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample size for this study is pragmatic, but the precision around any rates estimated among 4 patients (initial treatment phase) and 6 patients (expansion phase) is shown below.

For example, if 4 out of 4 patients experience CRC circulation time of 15 days to 29 days, the viable cell circulation time rate would be estimated at 100% (95% confidence intervals of 40% to 100%). If 10 out of 10 patients experience viable CRC circulation times, the estimate is (a little) more precise, at 100% (69%-100%). Rates will be estimated with exact confidence intervals.
From 10000 simulations, among the initial 4 patients, the probability of the trial expansion rules being met are estimated as follows, for a variety of true mean CRC circulation times and standard deviations (assuming the variable is normally distributed) is shown in the table below.

This indicates that if the true mean circulation time is 30 days, the study is very likely to proceed to the expansion phase (whether the SD is 5 or 10 days). If the true mean circulation time is 50 days, the study has a 91% probability that the expansion phase will not be pursued, as intended (if standard deviation is 5 days, and 51% probability if the standard deviation is 10 days).

If the true mean circulation time is only 10 days, the study has a 91% probability of having all four patients with an estimated mean circulation time of less than 20 days, as intended (if the standard deviation is 5 days).

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Withdrawn at the request of the funding company. No reason provided. There were no safety concerns.
Date of first participant enrolment
Anticipated
3/05/2018
Actual
Date of last participant enrolment
Anticipated
31/01/2019
Actual
Date of last data collection
Anticipated
29/06/2019
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10373 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 10374 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 22049 0
3000 - Melbourne
Recruitment postcode(s) [2] 22050 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 298964 0
Commercial sector/Industry
Name [1] 298964 0
Cell Therapies Pty Ltd.
Country [1] 298964 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Cell Therapies Pty Ltd
Address
Victorian Comprehensive Cancer Centre
Level 9
305 Grattan St
Melbourne
VIC 3000
Country
Australia
Secondary sponsor category [1] 298180 0
None
Name [1] 298180 0
Address [1] 298180 0
Country [1] 298180 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299897 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 299897 0
Victorian Comprehensive Cancer Centre
305 Grattan St
Melbourne
Victoria, Australia
3000
Ethics committee country [1] 299897 0
Australia
Date submitted for ethics approval [1] 299897 0
24/01/2018
Approval date [1] 299897 0
09/02/2018
Ethics approval number [1] 299897 0
HREC/17/PMCC/177

Summary
Brief summary
This is a phase I study investigating the mean circulation time, biodistribution and safety of an infusion of cultured red cells (CRC) in patients with MDS or patients in remission from haematologic malignancies
CRCs are enucleated red cells (reticulocytes) that are grown in culture from donor human haematopoietic stem cells. The collection, manufacturing and administration process used for CRC reduces the risks of infection and immune mediated transfusion reactions associated with traditional blood product administration.

This trial will be conducted in patients with very low and low-risk MDS or previous haematologic malignancy in remission and not on active treatment and who are able to undergo infusion of CRC and who fulfil all of the other protocol-defined eligibility criteria.

This is a single centre, Peter MacCallum Cancer Centre (PMCC)

Study outline:
The study will recruit four patients in the initial treatment phase. These patients will have a single infusion labelled cultured red cells at a dose of 0.7-1.5 x10^10 cells. They will be labelled with chromium and a cell surface marker called biotin. Following infusion the patients will undergo blood sampling, surface scanning, clinical review and physical examination at predefined intervals to determine mean circulation time of the red cells and evidence of distribution throughout the body.

The Data Safety Monitoring Board will review the safety data, circulation times and biodistribution after the fourth patient’s day 27 post infusion assessment has been completed and make a recommendation on safety to proceed to expansion phase. The Principal Investigator and the Clinical Study Oversight Group will determine need to pursue the expansion phase in which up to six additional patients may be recruited. Patients in the expansion phase will be treated and evaluated in the same way as those in the initial phase.

Up to 10 patients in total may be treated on this protocol.

Mean CRC circulation time (mCCT) and biodistribution will be determined from data collected in the first 27 days post infusion using the 51Cr label. Patients will be monitored until 120 post infusion to monitor for mCCT, alloantibody development and delayed transfusion associated reactions.

This Phase 1 study aims to determine the mean circulation time, biodistribution, safety and tolerability of CRCs in these patient groups.

It is anticipated that the technology in this study will be used in the development of Red-Cell Therapeutics that will act as a protein/drug delivery mechanism in the treatment of a wide range of diseases.
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 81910 0
A/Prof Simon Harrison
Address 81910 0
Level 7
Victorian Comprehensive Cancer Centre
305 Grattan St
Melbourne
Victoria
3000
Country 81910 0
Australia
Phone 81910 0
+61 3 855 97858
Fax 81910 0
Email 81910 0
[email protected]
Contact person for public queries
Name 81911 0
Myles Wright
Address 81911 0
Victorian Comprehensive Cancer Centre
305 Grattan St
Melbourne
Victoria 3000
Country 81911 0
Australia
Phone 81911 0
+61 3 855 95000
Fax 81911 0
Email 81911 0
[email protected]
Contact person for scientific queries
Name 81912 0
Myles Wright
Address 81912 0
Victorian Comprehensive Cancer Centre
305 Grattan St
Melbourne
Victoria 3000
Country 81912 0
Australia
Phone 81912 0
+61 3 855 95000
Fax 81912 0
Email 81912 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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