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Trial registered on ANZCTR


Registration number
ACTRN12623000104651
Ethics application status
Approved
Date submitted
8/11/2022
Date registered
30/01/2023
Date last updated
20/11/2023
Date data sharing statement initially provided
30/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase I Trial of Deflexifol for Refractory or Recurrent Paediatric Central Nervous System (CNS) Tumours
Scientific title
Phase I Trial of the Safety and Efficacy of Deflexifol for Refractory or Recurrent Paediatric Central Nervous System (CNS) Tumours
Secondary ID [1] 308235 0
None
Universal Trial Number (UTN)
Trial acronym
DART (Deflexifol At Relapse Trial)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Central Nervous System Tumour 327992 0
Ependymoma 327993 0
Diffuse Midline Glioma 327994 0
Diffuse Intrinsic Pontine Glioma 327995 0
Condition category
Condition code
Cancer 325050 325050 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase I multicentre study evaluating the use of Deflexifol in the treatment of children and young adults (greater than 12 months and less than or equal to 21 years) with refractory/recurrent central nervous system (CNS) tumours.

Deflexifol is a novel bioequivalent formulation of 5-fluorouracil and leucovorin that has been shown to be safe and effective in adults with advanced/ refractory solid tumours.

Phase I (or Part A) will be open to any participant with refractory or recurrent CNS tumours or diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG) after upfront radiotherapy. It will evaluate the safety profile and recommended phase II dose (RP2D) of deflexifol in participants with refractory/recurrent CNS tumours, or participants with newly diagnosed DIPG/DMG who have completed radiotherapy.

Deflexifol will be administered on Days 1 and 15 of a 28 day cycle. Deflexifol will initially be administered via an injection over 3-5 minutes (bolus), followed by a continuous intravenous infusion over 46 hours (infusional). Depending on the treating doctor and each participant’s condition, the treating doctor may elect to continue the treatment at home or in hospital. The following four dose levels will be tested, starting dose is Dose level 0:
Dose level -2: Deflexifol bolus dose of 525mg/m2 and infusional dose of 2400mg/m2 over 46 hours
Dose level -1: Deflexifol bolus dose of 525mg/m2 and infusional dose of 3000mg/m2 over 46 hours
Dose level 0: Deflexifol bolus dose of 525mg/m2 and infusional dose of 3400mg/m2 over 46 hours
Dose level +1: Deflexifol bolus dose of 525mg/m2 and infusional dose of 3800mg/ m2 over 46 hours

Each participant will be assigned a dose level at the start of treatment and will remain at the dose for the duration of the study. Participants may receive a minimum of 1 dose of study drug and a maximum of one year of study drug, as long as the participant is able to tolerate treatment.

Dosing will follow a dose de-escalation or escalation scheme which will be determined by biological effect of the drug (measured in participant blood samples) and levels of toxicity (measured by dose limiting toxicity and adverse event observed). A recommended phase 2 dose (RP2D) will be determined in this Phase I study.
Intervention code [1] 324691 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332874 0
Frequency, severity and relatedness of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), including dose-limiting toxicities (DLTs), in children and young adults receiving deflexifol. Adverse events will be assessed via clinical examination and are graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Timepoint [1] 332874 0
Dose limiting toxicities (DLTs) are defined as any events that are possibly, probably or definitely attributable to deflexifol in the first 4 weeks of treatment (Cycle 1). Therefore DLT evaluation will be performed in Cycle 1. Treatment emergent adverse events (TEAEs) and severe adverse events (SAEs) will be monitored continuously during the 1 year treatment.
Secondary outcome [1] 414926 0
Identify the maximum tolerated dose (MTD) of deflexifol in paediatrics by presence of dose limiting toxicities during Cycle 1.
Timepoint [1] 414926 0
Dose limiting toxicities will be assessed and graded using the CTCAE v5.0 for the first 4 weeks of treatment (Cycle 1).
Secondary outcome [2] 414927 0
Identify the recommended phase 2 dose (RP2D) of deflexifol in paediatrics through assessment of adverse events (AEs). The paediatric RP2D will be based on the findings of the toxicity and activity profile in patients enrolled in this study.
Timepoint [2] 414927 0
AEs will be assessed through clinical assessment and graded using the CTCAE v5.0 every 2 weeks.

Eligibility
Key inclusion criteria
1. Written informed consent
2. Patients must be greater than 12 months and less than or equal to 21 years of age at the time of study enrolment
3. Patient must have histologic confirmation of CNS tumour that is refractory or recurrent based on radiologic or tissue diagnosis; and for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
4. Patient must have measurable disease as per RAPNO criteria and/or evaluable disease. For patients who have received prior radiation therapy, the irradiated lesion needs to have progressed since cessation of radiotherapy.
5. Karnofsky performance status greater than or equal to 50 for patients above 16 years old;; or Lansky performance status greater than or equal to 50 for patients less than or equal to 16 years old. Patients who are not able to walk due to paralysis, but who are sitting up in a wheelchair, are considered ambulatory for the purpose of performance score assessment
6. Life expectancy of greater than 6 weeks
7. Patients receiving corticosteroids will need to be on a stable, or reducing, dose of steroids for at least one week before enrolment
8. Fully recovered from acute toxic effects of all prior anti-cancer therapy
8a. Must not have received myelosuppressive chemotherapy within 21 days of study entry (42 days if prior nitrosourea or mitomycin-C)
8b. At least 7 days after the last dose of anti-cancer agents not known to be myelosuppressive. For agents that have known adverse events occurring beyond 7 days after last administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair
8c. At least 42 days after the completion of any type of immunotherapy, e.g. tumour vaccines
8d. At least 21 days after the last dose of a monoclonal antibody, and toxicities related to prior antibody therapy have recovered to less than or equal to grade 1
8e. At least 6 weeks after the completion of radiation therapy (including CSI). If palliative radiotherapy has been administered, then 2 weeks must have lapsed before the patient can commence on this trial, and this lesion cannot be used as the target lesion for assessment of treatment response
8f. 14 days or more from last long-acting haematopoietic growth factors (e.g. pegfilgrastim) or 7 days for short acting growth factor
9. Adequate function in bone marrow, renal and liver. Blood pressure within normal range for age
10. Patient must be or have been previously enrolled in the ZERO Childhood Cancer (ZERO) precision medicine trial or program
11. Female patient of childbearing potential must have a negative serum or urine pregnancy test at screening and prior to the beginning of each cycle. They must agree to use an effective method of contraception during the study period and for six months after treatment discontinuation
12. Fertile male patients must use an effective method of contraception during the study period and for six months after treatment discontinuation
Minimum age
12 Months
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Concomitant medications
1a. Patients who are currently receiving another investigational agent are not eligible
1b. Patients who are currently receiving other anti-cancer agents are not eligible
2. Any known Dihydropyrimidine dehydrogenase (DPD) deficiency
3. Prior solid organ transplantation
4. Uncontrolled infection
5. Pregnant or breastfeeding

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A rolling 6 design will be used to enrol a minimum of 6 patients and maximum of 24 patients. The rolling six trial design will be used for dose finding. Enrolment will be suspended after the first patient has been enrolled until completion of the DLT period. Following that, 2 to 6 patients can be concurrently enrolled onto a dose level, dependent upon: number of patients enrolled on the current dose level; number of patients who have experienced DLT at the current dose level; number of patients entered, but without tolerability data at the current dose level.

Analysis plan:
RAPNO criteria will be tabulated for each evaluation time point and for each dose level.

The incidence of all AEs and SAEs will be summarised separately for treatment groups by system organ class and preferred term. Additionally, the incidence of all AEs and SAEs will be summarised by severity and relationship to study treatment. Patients who terminate the study due to an AE will be listed.

Safety data (haematology, serum chemistry and vital signs) will be summarised with simple descriptive statistics (minimum, maximum and median).

A Statistical Analysis Plan (SAP) details the statistical evaluations. This is based on:
- Descriptive statistics for safety data (outlined above) based on each dose level
- PK analysis, per dose level, and anthropometric measures (height, weight, body surface area using the Mosteller formula)
- Preliminary efficacy analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2023
Actual
29/08/2023
Date of last participant enrolment
Anticipated
31/03/2025
Actual
Date of last data collection
Anticipated
31/03/2030
Actual
Sample size
Target
24
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 23409 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 23410 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 23411 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [4] 23412 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [5] 23413 0
Monash Children’s Hospital - Clayton
Recruitment hospital [6] 23414 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [7] 23415 0
Perth Children's Hospital - Nedlands
Recruitment hospital [8] 23416 0
Womens and Childrens Hospital - North Adelaide
Recruitment postcode(s) [1] 38809 0
2031 - Randwick
Recruitment postcode(s) [2] 38810 0
2145 - Westmead
Recruitment postcode(s) [3] 38811 0
2305 - New Lambton
Recruitment postcode(s) [4] 38812 0
3052 - Parkville
Recruitment postcode(s) [5] 38813 0
3168 - Clayton
Recruitment postcode(s) [6] 38814 0
4101 - South Brisbane
Recruitment postcode(s) [7] 38815 0
6009 - Nedlands
Recruitment postcode(s) [8] 38816 0
5006 - North Adelaide

Funding & Sponsors
Funding source category [1] 312487 0
Charities/Societies/Foundations
Name [1] 312487 0
Kids with Cancer Foundation
Country [1] 312487 0
Australia
Funding source category [2] 312488 0
Charities/Societies/Foundations
Name [2] 312488 0
Robert Connor Dawes Foundation
Country [2] 312488 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australian and New Zealand Children’s Haematology and Oncology Group (ANZCHOG)
Address
27-31 Wright Street, Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 314078 0
None
Name [1] 314078 0
Address [1] 314078 0
Country [1] 314078 0
Other collaborator category [1] 282516 0
Individual
Name [1] 282516 0
Dr Marion Mateos - Co-Principal Investigator
Address [1] 282516 0
Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick NSW 2031
Country [1] 282516 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311827 0
Sydney Children’s Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 311827 0
Corner Hawkesbury Road and Hainsworth Street, Westmead NSW 2145
Ethics committee country [1] 311827 0
Australia
Date submitted for ethics approval [1] 311827 0
Approval date [1] 311827 0
10/08/2022
Ethics approval number [1] 311827 0

Summary
Brief summary
This is a multicentre Phase I clinical trial to establish if Deflexifol is safe and effective in children, adolescents and young adults with recurrent or refractory brain tumours.

Who is it for?
Participants may be eligible for this study if they are older than 12 months and up to 21 years old and have a recurrent or refractory brain tumour; or newly diagnosed diffuse intrinsic pontine glioma (DIPG) or diffuse midline glioma (DMG) participants after completion of radiotherapy.

Study details
Participants will receive Deflexifol every 2 weeks for up to approximately one year, if there is ongoing clinical benefit. Deflexifol will be administered via an injection over 3-5 minutes (bolus), followed by a continuous intravenous infusion over 46 hours. Pharmacokinetics will be measured during the first 4 weeks and safety will be assessed throughout the course of treatment and during follow up visits. Participants will have physical examinations, blood tests, urine tests, echocardiogram, electrocardiogram (ECG) and MRI scans.

This study will test the safety and effectiveness of this new drug in children and adolescents in cases where treatment options are limited.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122510 0
Prof David Ziegler
Address 122510 0
Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick NSW 2031
Country 122510 0
Australia
Phone 122510 0
+61 2 9382 1730
Fax 122510 0
Email 122510 0
[email protected]
Contact person for public queries
Name 122511 0
Robyn Strong
Address 122511 0
ANZCHOG, Hudson Institute of Medical Research, 27-31 Wright St, Clayton VIC 3168
Country 122511 0
Australia
Phone 122511 0
+613 8572 2684
Fax 122511 0
Email 122511 0
[email protected]
Contact person for scientific queries
Name 122512 0
David Ziegler / Dr Marion Mateos
Address 122512 0
Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick NSW 2031
Country 122512 0
Australia
Phone 122512 0
+61 2 9382 1730
Fax 122512 0
Email 122512 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Aggregate results will be made available publicly.


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.