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Trial registered on ANZCTR


Registration number
ACTRN12618000297224
Ethics application status
Approved
Date submitted
12/02/2018
Date registered
28/02/2018
Date last updated
28/02/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1 Study of Infusional or Bolus Deflexifol in patients with advanced malignacy after failure of standard treatment
Scientific title
Deflexifol (A novel formulation of 5 fluorouracil) phase 1 standard 3:3 design dose escalation study of infusional and bolus schedules of Deflexifol after failure of standard treatment.
Secondary ID [1] 294008 0
TGA CTN 2014/0737
Universal Trial Number (UTN)
NA
Trial acronym
FP101
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Malignant Cancer 306521 0
Condition category
Condition code
Cancer 305633 305633 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
An open-label dose-escalation trial to assess the safety and tolerability of 5-fluorouracil, folinic acid (as its calcium salt) and 2-hydroxypropyl-ß-cyclodextrin combined in a single formulation, called “Deflexifol”, in patients with histologically confirmed malignancy. This study will be in 2 separate cohorts either Bolus or Infusional

Infusion treatment levels: (similar to the De Gramont regimen).below: with continuous Infusional treatment delivered via a CADD pump. in following level cohorts
Level 1 1200 mg/m2/46 hr.
Level 2 1800 mg/m2/46 hr.
Level 3 2400 mg/m2/46 hr.
Level 4 3000 mg/m2/46 hr.
Level 5 3600 mg/m2/46 hr.




Bolus delivery
Deflexifol will be given as a bolus injection within approximately 5 minutes similar to (Roswell Park regimen). The bolus injection will be given weekly for 6 weeks consecutively followed by a 2 week break, before patients are eligible for a repeat course of treatment.
Patients will be enrolled in escalating dose cohorts, as summarised below:
Level 1 375 mg/m2
Level 2 425 mg/m2
Level 3 475 mg/m2
Level 4 525 mg/m2
Level 5 575 mg/m2

Dose Escalation rules:
The first 3 patients will initially be entered at Dose Level 1 and if no dose limiting toxicity (DLT) is observed in the following two weeks then the next 3 patients will be entered at the next dose level.
As long as there are no DLTs, 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 develops DLT, then the 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. If 2 or more patients (out of 6) experience DLTs, dose escalation will be halted and that level will be declared the DLT dose level. The previous dose level will then be considered for expansion to 6 patients in order to confirm the maximum tolerated dose (MTD).
Intervention code [1] 300279 0
Treatment: Drugs
Comparator / control treatment
No control group Phase 1 study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304742 0
To determine the safety and tolerability of Deflexifol in patients with relapsed or refractory malignancy. 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 [1] 304742 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.
Secondary outcome [1] 342996 0
To assess response rate per RECIST 1,1 Criteria in subjects with relapsed or refractory malignancy
Timepoint [1] 342996 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] 342997 0
To determine the maximum tolerated dose of Deflexifol by continuous infusion and by IV bolus. 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 [2] 342997 0
Participants are reviewed weekly for the Bolus regimen prior each treatment. Participants on the Infusion regimen are reviewed 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 [3] 342998 0
To determine the pharmacokinetic profile of Deflexifol.
Blood samples are taken from both the bolus and infusional patients during the 1st and 6th dose of Deflexifol. The timings for Bolus are: (pre study drug administration 0 mins, 20mins, 60mins, 120mins and 24 hrs). The timings for the Infusional level are: pre study drug administration, 2hrs 45-46hrs) Area under the curve (AUC), clearance (CLR) and plasma half lives (t1/2) were estimated for each patient to assess PK variability and adequacy of dosing in comparison to historical data.
PK values are calculated by program "PK Functions for Microsoft Excel"using add ins of PK1 and PK2 functions to excel data analysis files.
Timepoint [3] 342998 0
Patients on Infusion Cohort: blood samples taken at Day 1 commencement of dosing regimen and Day 70 at the end of the dose regimen (Dose 6)
Patients on Bolus Cohort: blood samples taken at Day 1 commencement of dosing and Day 35 at the end of the dosing regimen (Dose 6)

Eligibility
Key inclusion criteria
• Histologically or cytologically confirmed malignancy
• Patients must have metastatic or locally advanced disease, evaluable or measurable by RECIST Criteria, for which standard curative or palliative treatments have failed.
• For patients who received prior treatments, the disease must have progressed
• Age : 18 years and older
• ECOG performance status 0-2
• Life expectancy of greater than or equal to 12 weeks.
• Satisfactory organ and marrow function as defined below:
o Satisfactory haematologic parameters: Hb greater than 10g/dL, WBC greater than 3.0, Platelets greater than 100.
o Satisfactory hepatic function: Total Bilirubin less than 2 x ULN (upper limit of normal for the institution, to be decided) (unless there is a documented history of Gilbert’s syndrome), AST greater than 5xULN, ALT less than 5xULN, INR less than 1.5xULN, Albumin greater than 30g/L.
o Satisfactory renal function: serum creatinine less than 1.5xULN and calculated creatinine clearance greater than 35 ml/min.
o If female of childbearing age, a negative bHCG.
• Female patients must agree to use contraception prior to study entry, for the duration of study participation and for 90 days after the last dose of study medication
• 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
Exclusion criteria
Patients who meet the following criteria will be excluded from the study:
• 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.
• Known deficiency of dihydropyrimidine dehydrogenase (DPD)
• History of severe reactions to 5-FU or fluoropyrimides (Grade 3 or 4 CTC criteria)
• Untreated brain metastases
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Deflexifol including 5-FU, FA and ß-CD
• Concurrent anti-cancer treatment is not permitted. However, supportive therapies such as bisphosphonates are allowed
• Patients who require aspirin
• 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
• Pregnancy or breastfeeding
• 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)
Allocation is not concealled
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
No 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. Escalating dose cohorts based on Dose Level 1: The first 3 patients are entered on this dose level, if there is no dose limiting toxicity (DLT) in the first three weeks from those patients the next 3 patients are entered at the next dose level. Patients will continue to be entered at increasing dose levels in groups of 3. If at any given dose level 1 out of 3 patients experiences a DLT, then dose escalation is halted. A further 3 patients will be recruited at this dose level if there are no further DLTs then dose escalation continues. If there are 2 or more patients (out of 6) dose escalation is stopped and this level is declared the DLT dose level. The previous dose level is then considered for expansion to 6 patients to confirm Maximum Tolerated Dose (MTD)
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
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
Actual
9/12/2014
Date of last participant enrolment
Anticipated
Actual
10/01/2016
Date of last data collection
Anticipated
Actual
5/09/2017
Sample size
Target
30
Accrual to date
Final
41
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 9998 0
Southern Medical Day Care Centre - Wollongong
Recruitment postcode(s) [1] 18837 0
2500 - West Wollongong
Recruitment postcode(s) [2] 18838 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 298634 0
Commercial sector/Industry
Name [1] 298634 0
FivePhusion
Country [1] 298634 0
Australia
Funding source category [2] 298645 0
University
Name [2] 298645 0
University of Wollongong
Country [2] 298645 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
FivePhusion
Address
34 Hill St
Austinmer
NSW 2515
Country
Australia
Secondary sponsor category [1] 297905 0
None
Name [1] 297905 0
Address [1] 297905 0
Country [1] 297905 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299594 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 299594 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 299594 0
Australia
Date submitted for ethics approval [1] 299594 0
21/05/2014
Approval date [1] 299594 0
29/09/2014
Ethics approval number [1] 299594 0
201405259

Summary
Brief summary
5 Fluorouracil (5fu) is administered in combination with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not possible because 5FU and LV are chemically incompatible. Collectively, these adverse events lead to poor patient outcomes due to treatment interruption and discontinuation. Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-ß-CD 100mg/ml, 5FU 15mg/ml & LV 1mg/ml) at physiological pH, was developed as an alternative. This trial is to test the safety and efficacy of Deflexifol when given as a bolus or infusion to patients that have failed standard of care. The main outcome of this trial is to establish the safety and efficacy of Deflexifol and determine a suitable dose for further study in a phase II trial
Trial website
NA
Trial related presentations / publications
Results presented in part at the ASCO 2017 Annual Meeting of the American Society of Clinical Oncology Chicago,IL, June 2-6, 2017: Ackland, S.P., Garg, M.B., Ranson, M., Jokela, R., Brungs, D., Aghmesheh, M., Tafreshi, A., Ranson, R.D., Parker, S., De Souza, P.L. & Clingan, P.R. 2017, "Deflexifol (a novel formulation of 5FU): Pharmacokinetics in a phase 1 trial in comparison to 5FU", JCO, vol. 35, no. 15, pp. 2530-2530.

Clingan, P.R., Ackland, S.P., Ranson, M., Brungs, D., Aghmesheh, M., Tafreshi, A., Garg, M.B., Parker, S., Henderson, A., Jokela, R. & De Souza, P.L. 2017, "Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment", JCO, vol. 35, no. 15, pp. 2529-2529.

Clingan, P.R., Ackland, S.P., Ranson, M., De Souza, P., Tafreshi, A., Aghmesheh, M., Brungs, D., Garg, M.B., Parker, S. & Jokela, R. 2017, "Phase 1 study of infusional or bolus deflexifol (a novel formulation of 5FU, folinic acid, and cyclodextrin) after failure of standard treatment", JCO, vol. 35, no. 4, pp. TPS812-TPS812.
Public notes
NA

Contacts
Principal investigator
Name 80958 0
Prof Paul de Souza
Address 80958 0
Department of Medical Oncology
Liverpool Hospital,
Goulburn Street,
Liverpool NSW 2170
Country 80958 0
Australia
Phone 80958 0
+612 9616 4407
Fax 80958 0
+612 9616 4499
Email 80958 0
[email protected]
Contact person for public queries
Name 80959 0
Sue Parker
Address 80959 0
Southern Medical Day Care Centre
410 Crown St Wollongong
NSW 2500
Country 80959 0
Australia
Phone 80959 0
+ 612 4228 6200
Fax 80959 0
+ 61 2 42283563
Email 80959 0
[email protected]
Contact person for scientific queries
Name 80960 0
Philip Clingan
Address 80960 0
Southern Medical Day Care Centre
410 Crown St Wollongong
NSW 2500
Country 80960 0
Australia
Phone 80960 0
+ 61 24227 3733
Fax 80960 0
+612 4228 3563
Email 80960 0
[email protected]

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