A Phase 1 Study of Deflexifol in patients with advanced malignancy after failure of standard treatment
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
Detsamma Investments Pty Ltd
19 participants
Mar 9, 2020
Interventional
Conditions
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.
Eligibility
Inclusion Criteria8
- Histologically or cytologically confirmed malignancy
- Patients have metastatic or locally advanced disease, for which standard of care treatment has failed.
- Age 18 or above
- ECOG performance status of 0-2
- Life expectancy of greater than 12 weeks
- 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
- 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%.
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria9
- 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 fluoropyrimidines (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
- 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
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Interventions
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.
Locations(1)
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ACTRN12619001533189