A Phase 1 Study of Infusional or Bolus Deflexifol in patients with advanced malignacy after failure of standard treatment
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.
FivePhusion
30 participants
Dec 9, 2014
Interventional
Conditions
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
Eligibility
Inclusion Criteria13
- 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
Exclusion Criteria11
- 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
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Interventions
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).
Locations(1)
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ACTRN12618000297224