None listed
Conditions
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.
Interventions
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 recurren
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.
Sponsors
Australian and New Zealand Children’s Haematology and Oncology Group (ANZCHOG)
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
12 Months to 21 Years
Healthy volunteers
No
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
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
Outcome results
None listed