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Trial registered on ANZCTR


Registration number
ACTRN12619001533189
Ethics application status
Approved
Date submitted
25/10/2019
Date registered
6/11/2019
Date last updated
1/06/2023
Date data sharing statement initially provided
6/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Study of Deflexifol in patients with advanced malignancy after failure of standard treatment
Scientific title
A Phase 1 Study of Deflexifol: To determine pharmacokinetic (PK) in
patients administered a combined dose of bolus and continuous 46hr
infusion of Deflexifol in patients with advanced malignancy after failure of
standard treatment
Secondary ID [1] 299648 0
TGA CT-2019-CTN-02849-1
Universal Trial Number (UTN)
U1111-1242-5738
Trial acronym
FP101A
Linked study record
This follows on from the completed study ACTRN12618000297224

Health condition
Health condition(s) or problem(s) studied:
Advanced Malignant Cancer 314980 0
Condition category
Condition code
Cancer 313316 313316 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
An open-label study to determine the pharmacokinetic properties and evaluate safety of a combined bolus and 46 hr. continuous infusion dose schedule of Deflexifol in a traditional 3+3 dose escalation design. Deflexifol is 5-fluorouracil, folinic acid (as its calcium salt) and 2-hydroxypropyl-ß-cyclodextrin combined in a single formulation. This study will determine the feasibility of moving to a Phase II randomised two arm efficacy study.

Patients will receive 6 cycles of treatment, with one cycle every 2 weeks. A cycle comprises 2 days of treatment followed by 12 days without treatment.
Doses will be administered by nurses at a private hospital in Wollongong, NSW, the Southern Medical Day Care Centre.

The following dose levels will be tested:

Level 1:
Bolus Dose of Deflexifol 525mg/m2 followed immediately by an Infusional Dose of Deflexifol 2400mg/m2 over 46 hours
Level 2:
Bolus Dose of Deflexifol 525mg/m2 followed immediately by an Infusional Dose of Deflexifol 3000mg/m2 over 46 hours
Level 3:
Bolus Dose of Deflexifol 525mg/m2 followed immediately by an Infusional Dose of Deflexifol 3400mg/m2 over 46 hours
Level 4:
Bolus Dose of Deflexifol 525mg/m2 followed immediately by an Infusional Dose of Deflexifol 3800mg/m2 over 46 hours

Dose Escalation Rules:
Patients will be entered in escalating dose cohorts as listed below. The first 3 patients will
initially be entered at Dose Level 1. If there is no dose limiting toxicity (DLT) observed after two weeks from those first three patients, the next 3 patients will be entered at the next dose level. Whilst there are no DLTs on a dose level, new patients will continue to be entered at increasing dose levels in groups of three. If at any given dose level, at least 1/3 patients develop a DLT, then dose escalation will halt temporarily and a further 3 patients will be recruited at the same dose level. If there are no further DLTs, then dose escalation will continue until Dose Level 4. If there are 2 or more patients (out of 6) experience DLTs, dose escalation will be halted and that level will be declared the Dose Limiting Toxicity dose level. The previous dose level will then be considered for expansion to 6 patients in order to confirm that it is the maximum tolerated dose (MTD). If there are no further DLTs at that level, this is the dose that will be explored in Phase II/III studies.

Duration of Treatment
In the absence of treatment delays due to adverse events, the patient may elect to continue treatment after the study up to 6 months or until one of the following occurs:
Disease progression
Intercurrent illness that prevents further administration of treatment
Unacceptable adverse event
Patient decides to withdraw from study
General or specific changes in the patient’s condition that render the patient unacceptable for further treatment in the judgement of the treating doctor or investigator.
Intervention code [1] 315906 0
Treatment: Drugs
Comparator / control treatment
No control group - a phase 1 study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321792 0
To determine the pharmacokinetic profile of bolus and continuous infusion Deflexifol as a combination therapy in patients with relapsed or refractory malignancy.
Blood plasma levels of 5-FU and its metabolite 5-fluoro-5,6-dihydrouracil (5-FUH2) will be measured using HPLC (Ackland et al,1997) Area under the curve (AUC), clearance (CLR) and plasma half-life (t1/2) will be assessed for each patient to determine PK variability and adequacy of dosing.
Timepoint [1] 321792 0
There are 6 PK blood sample collection time points at Cycle 1 and Cycle 2.
Sample 1: Prior to start of bolus dose (baseline)
Sample 2: Immediately after bolus dose (end of
bolus)
Sample 3: 120 mins (2 hrs) post start of infusion
time
Sample 4: 150 mins (2.5 hrs) post start of infusion
time
Sample 5: 180 mins (3 hrs) post start of infusion
time
Sample 6: 45 hours post start of infusion time
whilst infusion is still running (day 3)
Primary outcome [2] 321793 0
To evaluate the safety of the combined bolus and continuous infusion Deflexifol dose schedule.
Safety will be evaluated by monitoring Adverse Events (AEs), vital signs, haematology parameters, clinical chemistry profile and physical examinations.

The following AE’s are common (occurring in greater than 30%) of patients taking 5-FU.
Diarrhoea; Nausea and possible occasional vomiting; Mouth soreness or mucositis; Poor appetite; Watery eyes, sensitivity to light (photophobia); Taste changes, metallic taste in mouth during infusion; Discoloration along vein through which the medication is given; and Low blood counts. White and red blood cells and platelets may temporarily decrease, this can lead to increased risk of infection, enema and or bleeding.
Timepoint [2] 321793 0
All adverse events graded according to National Cancer Institute Common Terminology for Adverse Events version (CTACE)V4.03. Adverse event monitoring continued for four weeks after the final treatment. All patients will be reviewed by the investigator prior to the commencement of each cycle of treatment physical exams, vitals signs, weight, performance status CBCw/differential platelets and serum chemistry will be performed as appropriate but generally on a weekly basis.
Primary outcome [3] 321794 0
To determine Maximum Tolerated Dose (MTD) of combined bolus and continuous infusion Deflexifol.
The maximum tolerated dose is defined as 2 out of 6 participants experience
Dose limiting toxicity including: Any grade 3 diarrhoea, failing maximal anti-diarrhoeal medications. Any grade 3 or 4 non-hematologic toxicity: Common Terminology Criteria for Adverse Events (CTACE) if 2 participants experience any of the above toxicities this dose level is declared the dose limiting toxicity dose (DLT dose).The previous dose level is then expanded to 6 participants to confirm the maximum tolerated dose.
Timepoint [3] 321794 0
Participants are reviewed by their doctor every two weeks prior to each treatment. Treatment continues up to 6 cycles of treatment or until one of the following:
1. Disease Progression
2. Intercurrent illness that prevents further administration or treatment
3. Unacceptable adverse events
4. Patient decided to withdraw from the study
5. General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgement of the investigator.
Secondary outcome [1] 376224 0
To determine the response rate (RR per RECIST 1.1 criteria)
Timepoint [1] 376224 0
CT Scan per RECIST1.1 at 8 weeks then at the completion of treatment. Responses are evaluated by Response Evaluation Criteria in solid tumours approximately 6-8 weeks from baseline treatment.
Secondary outcome [2] 376225 0
Determine Progression Free Survival (disease progression or death).
Progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur. J. Cancer 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
Timepoint [2] 376225 0
Patients will be re-evaluated for response every 8 weeks.
In addition, confirmatory scans will also be obtained not less than 4 weeks following initial documentation of objective response.

Eligibility
Key inclusion criteria
1. Histologically or cytologically confirmed malignancy
2. Patients have metastatic or locally advanced disease, for which standard of care treatment has failed.
3. Age 18 or above
4. ECOG performance status of 0-2
5. Life expectancy of greater than 12 weeks
6. Satisfactory organ and marrow function as defined below: Satisfactory haematologic parameters: Hb>10g/dL, WBC>3.0, Platelets>100 Satisfactory hepatic function: Total Bilirubin less than 2 x ULN (upper limit of normal for the institution) (unless there is a documented history of Gilbert’s syndrome), AST <5xULN, ALT<5xULN, INR<1.5xULN, Satisfactory renal function: serum creatinine < 1.5xULN and calculated creatinine clearance > 35 ml/min. If female of childbearing potential , a negative pregnancy test
7. Female patients must agree to use contraception prior to entry to study for duration of study participation and for 90 days after the last dose of medication. Contraception must be highly effective with a failure of less then 1%.
8. Ability to understand and the willingness to sign a written informed consent document.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or the presence of adverse events due to agents administered more than 4 weeks earlier.
2. Known deficiency of dihydropyrimidine dehydrogenase (DPD)
3. History of severe reactions to 5-FU or fluoropyrimidines (Grade 3 or 4 CTC criteria)
4. Untreated brain metastases
5. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Deflexifol including 5-FU, FA and ß-CD
6. Concurrent anti-cancer treatment is not permitted. However, supportive therapies such as bisphosphonates are allowed
7. Uncontrolled, inter-current illness including, but not limited to ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; transient ischemic attacks (TIA) or intermittent claudication; ventricular arrhythmias; atrial flutter or atrial fibrillation; pathologic sinus bradycardia (<60 bpm); heart block (excluding 1st degree block) or congenital long QT syndrome; or psychiatric illness/social situations that would limit compliance with study requirements
8. Pregnancy or breastfeeding
9. HIV-positive

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Standard 3:3 dose escalation study.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Descriptive statistics on safety data (ECG, haematology,serum chemistry and vital signs)
RECIST criteria will be tabulated by evaluation time and dose of drug. The Kaplan and Meir method will be used to calculate progression free and overall survival.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
8/11/2019
Actual
9/03/2020
Date of last participant enrolment
Anticipated
1/09/2022
Actual
20/03/2023
Date of last data collection
Anticipated
31/12/2022
Actual
22/05/2023
Sample size
Target
19
Accrual to date
Final
19
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 28332 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 304120 0
Commercial sector/Industry
Name [1] 304120 0
Detsamma Investments Pty Ltd
Country [1] 304120 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Detsamma Investments Pty Ltd
Address
34 Hill St,
Austinmer NSW 2515
Country
Australia
Secondary sponsor category [1] 304336 0
None
Name [1] 304336 0
Address [1] 304336 0
Country [1] 304336 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304607 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 304607 0
123 Glen Osmond Road, Eastwood SA 5063
Ethics committee country [1] 304607 0
Australia
Date submitted for ethics approval [1] 304607 0
21/08/2019
Approval date [1] 304607 0
17/10/2019
Ethics approval number [1] 304607 0
2019-07-651-A-1

Summary
Brief summary
This study will determine the pharmacokinetic properties of Deflexifol, as well as test the safety and efficacy of Deflexifol when given as a bolus followed by infusion to patients that have failed standard of care

Who is it for?
You may be eligible to join this study if you are aged 18 and above and have metastatic or locally advanced malignancy for which standard of care treatment has failed.

Study details
Participants in this study are allocated to one of 4 dose levels of Deflexifol, administered to participants in a combined bolus and infusion. Patients will receive 6 cycles of one dose level, with one treatment occurring every 2 weeks.

Pharmacokinetics will be measured during the first 2 cycles, and safety will be assessed every 2 weeks over the 6 cycles of treatment. A follow up visit will be conducted 30 days after the last dose of trial treatment.

It is hoped this trial will determine a suitable dose for further study of Deflexifol in a phase II trial.
Trial website
NA
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97562 0
A/Prof Daniel Brungs
Address 97562 0
Southern Medical Day Care Centre
410 Crown Street
Wollongong NSW 2500
Country 97562 0
Australia
Phone 97562 0
+61 2 4227 3733
Fax 97562 0
+61 2 4228 3563
Email 97562 0
[email protected]
Contact person for public queries
Name 97563 0
Sue Parker
Address 97563 0
Southern Medical Day Care Centre
410 Crown Street
Wollongong NSW 2500
Country 97563 0
Australia
Phone 97563 0
+61 2 4227 3733
Fax 97563 0
+61 2 4228 3563
Email 97563 0
[email protected]
Contact person for scientific queries
Name 97564 0
Phil Clingan
Address 97564 0
Southern Medical Day Care Centre
410 Crown Street
Wollongong NSW 2500
Country 97564 0
Australia
Phone 97564 0
+61 2 4227 3733
Fax 97564 0
+61 2 4228 3563
Email 97564 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
All data will be compiled into a final report that is the property of the sponsor company. All participant data will be provided in summary format and result of the study only will be reported


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
5467Informed consent form    378626-(Uploaded-25-10-2019-15-47-50)-Study-related document.pdf



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.