None listed
Conditions
Brief summary
This study will evaluate the safety and tolerability of combining the 3 drugs, vinorelbine, cyclophosphamide, and Rapamycin, in children with recurrent/refractory malignant disease. Who is it for? You (or your child) may be eligible to join this study if you/they are aged less than 22 years of age and have been diagnosed with any of the following solid tumours/malignancies: all brain tumours, Rhabdomyosarcoma, Soft tissue sarcomas, Osteogenic sarcoma, Ewing sarcoma, Neuroblastoma, Wilms’ tumour. The disease must have either relapsed or not responded to initial therapy. Trial details All participants in this trial will undergo treatment with a combination of the three drugs vinorelbine, cyclophosphamide, and rapamycin. Cyclophosphamide is administered one per day orally, rapamycin is administered twice per day orally, and vinorelbine will be administered on days 1, 8 and 15 of each 28 day cycle intravenously (i.e. into the vein). This cycle will be repeated every 28 days. If the initial dose level is tolerated by patients, then it will be increased for the next patient group in order to determine the optimum dose combination for both heavily pre-treated and less heavily pre-treated participants. In addition to evaluating the toxicity of this drug regimen and determining a dosage range, the potential efficacy of the regimen will be assessed. All participants will be regularly monitored and assessed for a period of up to 5 years in order to evaluate the safety and tolerability of this treatment.
Interventions
Chemotherapy Days 1-28:
Cyclophosphamide once per day orally according to allocated dose level as per dose levels below.
Rapamycin orally at an initial dosage of 0.8mg/m2/dose twice per day. Dosing will be pharmacologically adjusted on a weekly basis to maintain a trough Rapamycin level between 10 and 15 ng/ml.
Days 1,8,15: vinorelbine intravenously at allocated dose level as per dose levels below.
Repeat cycle every 28 days.
Dose Level 0 = 20 mg/m2/day of cyclophosphamide and 20 mg/m2/week da
Chemotherapy Days 1-28: Cyclophosphamide once per day orally according to allocated dose level as per dose levels below. Rapamycin orally at an initial dosage of 0.8mg/m2/dose twice per day. Dosing will be pharmacologically adjusted on a weekly basis to maintain a trough Rapamycin level between 10 and 15 ng/ml. Days 1,8,15: vinorelbine intravenously at allocated dose level as per dose levels below. Repeat cycle every 28 days. Dose Level 0 = 20 mg/m2/day of cyclophosphamide and 20 mg/m2/week days 1,8,15 of vinorelbine. Dose Level 1 = 25 mg/m2/day of cyclophosphamide and 20 mg/m2/week days 1,8,15 of vinorelbine. Dose Level 2 = 25 mg/m2/day of cyclophosphamide and 25 mg/m2/week days 1,8,15 of vinorelbine. Dose Level -1 (if the first dose level "Dose Level 0" is not tolerated) = 15 mg/m2/day of cyclophosphamide and 10 mg/m2/week days 1,8,15 of vinorelbine. Each cycle will be considered to be 28 days. Proceed to 2nd and subsequent cycles if platelet counts are acceptable, all toxicities from previous treatment cycles have been resolved and there is no evidence of disease progression. In the absence of tumour progression and/or unacceptable toxicities, the treatment cycles can continue at the treating doctor’s discretion. Sirolimus levels will be measured by blood tests. A take home medication diary will be used to record any take home tablets. Participants remain on the same allocated dose level throughout treatment. There is no dose escalation for individual patients.
Sponsors
Australian New Zealand Childrens Haematology Oncology Group
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
0 to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must be < 22 years of age at the time of study entry. 2. Patients must have had histologic verification of the solid tumour/malignancy either at the time of original diagnosis or at relapse (excluding brain stem and optic pathway tumours). Participants are not required to have measurable disease at the time of study entry. The following histologies are eligible: All brain tumours, Rhabdomyosarcoma, Soft tissue sarcomas, Osteogenic sarcoma, Ewing sarcoma, Neuroblastoma, Wilms’ tumour. 3. Patient’s disease must be relapsed or refractory following initial therapy. 4. Patient’s disease must be one for which there is no curative therapy. 5. Performance: Karnofsky greater than or equal 50% for patients 16 years of age and over and Lansky greater than or equal 50 for patients less than 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. 6. Life expectancy must be greater than or equal 8 weeks 7. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea). Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. XRT: greater than or equal 2 wks for local palliative XRT (small port); greater than or equal 6 months must have elapsed if prior craniospinal XRT or if greater than or equal 50% of the pelvis has been radiated; greater than or equal 6 wks must have elapsed if other substantial BM radiation. Patients with recurrent brain tumours should be greater than or equal 8 weeks from completion of standard fraction radiation unless there is biopsy proof of the presence of recurrent tumour. Patients who underwent radiosurgery within 9 months must have documentation of progressive disease either by biopsy, PET scan or MR spectroscopy. 8. Concomitant medications: Growth factor(s) must not have received within 1 week of entry onto this study. Systemic corticosteroid therapy is permissible only in patients with CNS tumours for treatment of increased intracranial pressure or symptomatic tumour oedema. Patients with CNS tumours who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to study entry. 9. Organ Function Requirements: Adequate Bone Marrow Function Defined as: Peripheral absolute neutrophil count (ANC) > 1000/microL, Platelet count > 100,000/microL (transfusion independent, i.e. patients must not have received platelet transfusions within 7 days of enrolment), Haemoglobin > 80.0 g/L (may receive RBC transfusions). Adequate Renal Function Defined As: Creatinine clearance or radioisotope GFR greater than or equal 70ml/min/1.73 m2 and a normal serum creatinine based on age. Adequate Liver Function Defined As: Total bilirubin < 1.5 x upper limit of normal (ULN) for age, and ALT < 2.5 x upper limit of normal (ULN) for age and albumin greater than or equal 20 g/L. 10. All patients and/or their parents or legal guardians must sign a written informed consent. All institutional ethics requirements for human studies must be met prior to patient accrual.
Exclusion criteria
1. Pregnant or lactating females are ineligible as the medications used in this protocol could be harmful to unborn children and infants. Pregnancy tests must be obtained in girls who are post-menarche. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. 2. Patients who have an uncontrolled infection are excluded from this study. 3. Patients who have previously received Rapamycin, Everolimus, Tacrolimus or Temsirolimus are excluded from this study.
Outcome results
None listed